local anesthetics have been shown to exhibit neuroprotective properties in vivo , during cerebral ischemia in gerbils [ fujitani et al . ( 1994 ), neurosci . lett ., 179 : 91 - 4 ; chen et al . ( 1998 ) brain res ., 4 : 16 ; adachi et al . ( 1999 ) brit . j . anaesth ; 83 : 472 , and in vitro , during an hypoxic episode in hippocampal neurons [ lucas et al . ( 1989 ) j . neurosci . methods , 28 : 47 ; liu et al . ( 1997 ) anesthesiolog , 87 : 1470 ; raley - susman et al ., ( 2001 ) j . neurophysiol . 86 : 2715 - 26 .]. concomitantly , procaine and lidocaine have been show to inhibit nmda receptor activity [ nishizawa et al ., ( 2002 ) anesth . analg ., 94 : 325 - 30 ,], suppress the anoxia - induced increase of the intracellular calcium concentration in gerbil hippocampus [ liu et al ., ( 1997 ) anesthesiology , 87 : 1470 ] and prevent the ischemia - triggered increase of extracellular glutamate concentration in gerbil brain [ fujitani et al ., 1994 , cited above ]. as used herein , the term “ treatment of alzheimer &# 39 ; s disease ” includes inhibiting the development of ad in a subject exhibiting at least one of the symptoms of the onset of ad , or who is likely to develop ad , as well as the ability to halt or slow the progression of ad , or to reduce or alleviate at least one of the symptoms of ad . the term “ treatment ” as used with respect to any neuropathology , such as multiple sclerosis , vascular dementia , age - related depression and mood swings and the like , is also intended to be defined in this manner . the following definitions are used , unless otherwise described : halo is fluoro , chloro , bromo , or iodo . alkyl , alkoxy , alkenyl , alkynyl , etc . denote both straight and branched groups ; but reference to an individual radical such as “ propyl ” embraces only the straight chain radical , a branched chain isomer such as “ isopropyl ” being specifically referred to . aryl denotes a phenyl radical or an ortho - fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic . heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing about 5 or 6 ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non - peroxide oxygen , sulfur , and n ( r 7 ) wherein r 7 is absent or is as defined above ; as well as a radical of an ortho - fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom , particularly a benz - derivative or one derived by fusing a propylene , trimethylene , or tetramethylene diradical thereto . it will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms . some compounds may exhibit polymorphism . it is to be understood that the present invention encompasses any racemic , optically - active , polymorphic , or stereoisomeric form , or mixtures thereof , of a compound of the invention , which possess the useful properties described herein , it being well known in the art how to prepare optically active forms ( for example , by resolution of the racemic form by recrystallization techniques , by synthesis from optically - active starting materials , by chiral synthesis , or by chromatographic separation using a chiral stationary phase ) and how to determine anti - toxin activity using the standard tests described herein , or using other similar tests which are well known in the art . specific and preferred values listed below for radicals , substituents , and ranges , are for illustration only ; they do not exclude other defined values or other values within defined ranges for the radicals and substituents . specifically , ( c 1 - c 6 ) alkyl can be methyl , ethyl , propyl , isopropyl , butyl , iso - butyl , sec - butyl , pentyl , 3 - pentyl , or hexyl ; ( c 3 - c 12 ) cycloalkyl can be monocyclic , bicyclic or tricyclic and includes cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , bicyclo [ 2 . 2 . 2 ] octanyl , norbornyl , adamantyl as well as various terpene and terpenoid structures . ( c 3 - c 12 ) cycloalkyl ( c 1 - c 6 ) alkyl includes the foregoing cycloalkyl and can be cyclopropylmethyl , cyclobutylmethyl , cyclopentylmethyl , cyclohexylmethyl , 2 - cyclopropylethyl , 2 - cyclobutylethyl , 2 - cyclopentylethyl , or 2 - cyclohexylethyl . heterocycloalkyl and ( heterocycloalkyl ) alkyl include the foregoing cycloalkyl wherein the cycloalkyl ring system is monocyclic , bicyclic or tricyclic and optionally comprises 1 - 2 s , non - peroxide o or n ( r 7 ) as well as 2 - 12 ring carbon atoms ; such as morpholinyl , piperidinyl , piperazinyl , indanyl , 1 , 3 - dithian - 2 - yl , and the like ; the cycloalkyl ring system optionally includes 1 - 3 double bonds or epoxy moieties and optionally is substituted with 1 - 30h , ( c 1 - c 6 ) alkanoyloxy , ( co ), ( c 1 - c 6 ) alkyl or ( c 2 - c 6 ) alkynyl . ( c 1 - c 6 ) alkoxy can be methoxy , ethoxy , propoxy , isopropoxy , butoxy , iso - butoxy , sec - butoxy , pentoxy , 3 - pentoxy , or hexyloxy ; ( c 2 - c 6 ) alkenyl can be vinyl , allyl , 1 - propenyl , 2 - propenyl , 1 - butenyl , 2 - butenyl , 3 - butenyl , 1 ,- pentenyl , 2 - pentenyl , 3 - pentenyl , 4 - pentenyl , 1 - hexenyl , 2 - hexenyl , 3 - hexenyl , 4 - hexenyl , or 5 - hexenyl ; ( c 2 - c 6 ) alkynyl can be ethynyl , 1 - propynyl , 2 - propynyl , 1 - butynyl , 2 - butynyl , 3 - butynyl , 1 - pentynyl , 2 - pentynyl , 3 - pentynyl , 4 - pentynyl , 1 - hexynyl , 2 - hexynyl , 3 - hexynyl , 4 - hexynyl , or 5 - hexynyl ; ( c 1 - c 6 ) alkanoyl can be formyl , acetyl , propanoyl or butanoyl ; halo ( c 1 - c 6 ) alkyl can be iodomethyl , bromomethyl , chloromethyl , fluoromethyl , trifluoromethyl , 2 - chloroethyl , 2 - fluoroethyl , 2 , 2 , 2 - trifluoroethyl , or pentafluoroethyl ; hydroxy ( c 1 - c 6 ) alkyl can be alkyl substituted with 1 or 20h groups , such as hydroxymethyl , 1 - hydroxyethyl , 2 - hydroxyethyl , 1 - hydroxypropyl , 2 - hydroxypropyl , 3 - hydroxypropyl , 1 - hydroxybutyl , 4 - hydroxybutyl , 3 , 4 - dihydroxybutyl , 1 - hydroxypentyl , 5 - hydroxypentyl , 1 - hydroxyhexyl , or 6 - hydroxyhexyl ; ( c 1 - c 6 ) alkoxycarbonyl can be methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , pentoxycarbonyl , or hexyloxycarbonyl ; ( c 1 - c 6 ) alkylthio can be methylthio , ethylthio , propylthio , isopropylthio , butylthio , isobutylthio , pentylthio , or hexylthio ; ( c 2 - c 6 ) alkanoyloxy can be acetoxy , propanoyloxy , butanoyloxy , isobutanoyloxy , pentanoyloxy , or hexanoyloxy ; aryl can be phenyl , indenyl , indanyl , or naphthyl ; and heteroaryl can be furyl , imidazolyl , triazolyl , triazinyl , oxazolyl , isoxazolyl , thiazolyl , isothiazolyl , pyrazolyl , pyrrolyl , pyrazinyl , tetrazolyl , pyridyl , ( or its n - oxide ), thienyl , pyrimidinyl ( or its n - oxide ), 1h - indolyl , isoquinolyl ( or its n - oxide ) or quinolyl ( or its n - oxide ). local or topical anesthetics , all of which are believed to be useful in the present invention , are an art - recognized class of drugs which temporarily interrupt mammalian nerve transmissions . they can generally be grouped into three chemical classifications structurally ; the n - arylamides or carboxamides , such as lidocaine ; the aminoalkylbenzoates , such as procaine , benoxinate and proparacaine , and the aminoalkylbenzamides , such as procainamide . preferred n - arylamides comprise the n -( c 7 - c 22 ) arylamides of amino - substituted ( c 1 - c 5 ) carboxylic acids , e . g ., n -[( mono or di -( c 1 - c 4 ) alkyl ) phenyl ] amides of aliphatic ( c 1 - c 5 ) carboxylic acids , which acids are preferably substituted with the moiety ( r 7 )( r 8 ) n —, wherein r 7 is h or ( c 1 - c 5 ) alkyl and r 8 is ( c 1 - c 5 ) alkyl . for example , a preferred carboxylic acid can have the general formula ( r 7 )( r 8 ) n ( x ) co 2 h where r 7 and r 8 are as defined above and x is a branched - or straight - chain ( c 1 - c 5 ) alkylene group such as 1 , 1 - ethylene , 1 , 2 - ethylene , methylene , 2 , 2 - propylene , 1 , 3 - propylene , and the like . another preferred class of n - arylamides are the n -( mono - or di -( c 1 - c 4 ) alkyl ) phenyl ] amides of 5 - or 6 - membered - heterocycloaliphatic carboxylic acids , which acids comprise one or two [( c 1 - c 4 ) alkyl - substituted ] n atoms , i . e ., n - butylpiperidine - 2 - carboxylic acid . useful topical anesthetics of this class include lidocaine (( 2 - diethylamino )- n -( 2 , 6 - dimethylphenyl )- acetamide ) ( see lofgren et al . ( u . s . pat . no . 2 , 441 , 498 ), may & amp ; baker ( british patent no . 706409 ) and macfarlane & amp ; co . ( british patent no . 758 , 224 )); bupivacaine ( 1 - butyl - n -( 2 , 6 - dimethylphenyl )- 2 - piperidinecarboxyamide ) ( see thuresson et al ., ( u . s . pat . no . 2 , 955 , 111 ) and sterling drug ( british patent nos . 1 , 166 , 802 and 1 , 180 , 712 )); mepivacaine ( 2 - piperidinecarboxyamide , n -( 2 , 6 - dimethylphenyl )- 1 - methyl ), etidocaine ( n -( 2 , 6 - dimethylphenyl )- 2 -( ethylpropylamino ) butanamide ; see , astra ( german patent no . 2162744 )); dibucaine ( 3 - butoxy - n -[ 2 -( diethylamino ) ethyl ]- 4 - quinolinecarboxyamide ; miescher ( u . s . pat . no . 1 , 825 , 623 )); dyclonine ( 1 -( 4 - butoxyphenyl )- 3 -( 1 - piperidinyl - 1 - propanone )); prilocalne ( n -( 2 - methylphenyl )- 2 -( propylamino ) propanamide ); pyrrocaine ( 1 -( pyrrolidin - 1 - yl )- n -( 2 , 6 - dimethylphenyl ) acetamide , dimethylsoquin , diperodon , cocaine and its analogs ( see , carroll et al ., j . med . chem ., 34 , 2719 ( 1991 ); eur . j . pharmacol ., 184 , 329 ( 1990 ); and the pharmaceutically acceptable salts thereof . the aminoalkylbenzoates include esters between benzoic acids and alcohols of the general formula ( r 7 )( r 8 ) n ( alk ) oh , wherein alk is as defined above . r 7 is h or ( c 1 - c 4 )- alkyl , r 8 is ( c 1 - c 4 ) alkyl or r 7 and r 8 taken together with n are a 5 - or 6 - membered heterocyclic ring , optionally substituted by ( c 1 - c 3 ) alkyl or comprising an additional ring o — or n ( r 7 )- atom . the benzoic acid moiety can be the moiety ( r 9 )( r 10 ) arco 2 h wherein ar is an aromatic — c 6 h 2 - 4 radical “ phenylene ” and each r 9 and r 10 is individually h , halo , preferably cl ; ( r 5 )( h ) n —, h 2 n — or ( c 1 - c 5 ) alkoxy . ar can also be ( c 6 - c 12 ) heteroaryl , optionally substituted with r 9 and r 10 . useful topical anesthetics including chloroprocaine ( 4 - amino - 2 - chlorobenzoic acid 2 -( diethylamino ) ethyl ester ); procaine ( 4 - aminobenzoic acid 2 -( diethylamino ) ethyl ester ); tetracaine ( 4 -( butylamino ) benzoic acid 2 -( dimethylaminoethyl ester ; see shupe ( u . s . pat . no . 3 , 272 , 700 )); benoxinate ( 4 - amino - 3 - butoxybenzoic acid 2 -( diethylamino ) ethyl ester ( u . k . patent no . 654 , 484 )) proparacaine ( 3 - amino - 4 - propoxybenzoic acid 2 -( diethylamino ) ethyl ester ); isobucain ( 1 - propanol , 2 - methyl - 2 -[( 2 - methylpropyl ) amino ] benzoate ; meprylcaine ([( 2 - methyl )( 2 - propylamino ) propyl ] benzoate ; piperocaine (( 2 - methylpiperidin - 1 - ylpropyl ( benzoate )); propoxycaine ( 2 -( diethylamino ) ethyl -([ 2 ′- methyl - 4 ′- amino ] benzoate )); butacaine ((( 3 - dibutylamio ) propyl )-( 2 ′- aminobenzoate )); cyclomethylcaine ((( 3 - 2 ′- methylpiperidine - 1 - yl )) propyl )-[ 4 ′- cyclohexyloxy - benzoate ]); hexylcaine (([ 2 - cyclohexylamino )( 1 - methyl )] ethyl )( benzoate ) and proparacaine ((( 2 - diethylamino ) ethyl ) [( 4 ′- propyloxy - 3 ′- amino ) benzoate ]). preferred salts include the amino addition salts of inorganic and organic acids , e . g ., the hydrochloride , hydrobromide , sulfate , oxalate , fumarate , citrate , malate , propionate and phosphate salts . the hydrochloride and sulfate salts are preferred for use in the present invention . these topical anesthetics and the salts thereof are discussed in detail in remington &# 39 ; s pharmaceutical sciences , a . osol , ed ., mack pub . co ., easton , pa . ( 16 th ed . 1980 ), and in the merck index ( 11 th ed . 1989 ). a specific value for r 1 in formula i or ii , above is h , ( c 2 - c 4 ) alkyl , ( c 2 - c 4 ) alkoxy , ( c 3 - c 6 ) cycloalkoxy , or ( c 3 - c 6 ) heterocycloalkyl . a specific value for r 4 is h or n ( r 5 )( r 6 ), which is preferably is amino or ( c 1 - c 4 ) alkylamino . a specific value for n ( r 7 )( r 8 ) is dimethylamino , diethylamino , dipropylamino , cyclohexylamino , or propylamino . a specific value for ( alk ) is —( ch 2 ) 1 - 3 —. a preferred group of compounds are compounds of formula ii which are aminoalkyl benzoates . another preferred group of compounds are compounds of formula ii which are n - aminoalkyl - benzamides , or ( n - aryl ) alkylbenzamides . a preferred compound of the invention is lidocaine , procaine , tetracaine or procainamide , or an analog thereof . benzamide compounds of formula ii can be prepared as shown in scheme a , below . benzoates can be prepared by replacing amine iii with the corresponding alcohol and using it to esterify iii . groups r 1 , r 2 and / or r 3 on phenyl that are reactive with socl 2 , or ( c ( o ) cl ) 2 such as hydroxy - containing or thio - containing groups can be protected with removable protecting groups such as ethyoxyethyl , thp , ( c 1 - c 4 ) 3 silyl and the like . protected oh and hydroxylalkyl groups can be deprotected , and converted into halo , cn , alkoxycarbonyl , alkanoyloxy and alkanoyl by methods known to the art of organic synthesis . protected amino groups can be deprotected and converted into n ( r 6 )( r 7 ) by methods known to the art . if necessary the c ═ o group can be protected and / or reduced during these conversions , then deprotected and reoxidized to c ═ o . see , for example , i . t . harrison , compendium of organic synthetic reactions , wiley - interscience , n . y . ( 1971 ); l . f . fieser et al ., reagents for organic synthesis , john wiley & amp ; sons , inc ., n . y . ( 1967 ), and u . s . pat . no . 5 , 411 , 965 . in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts , administration of the compounds as salts may be appropriate . examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion , for example , tosylate , methanesulfonate , acetate , citrate , malonate , tartarate , succinate , benzoate , ascorbate , α - ketoglutarate , and α - glycerophosphate . suitable inorganic salts may also be formed , including hydrochloride , sulfate , nitrate , bicarbonate , and carbonate salts . pharmaceutically acceptable salts may be obtained using standard procedures well known in the art , for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion . alkali metal ( for example , sodium , potassium or lithium ), alkaline earth metal ( for example calcium or magnesium ) or zinc salts can also be made . the compounds of formula i can be formulated as pharmaceutical compositions and administered to a mammalian host , such as a human patient in a variety of forms adapted to the chosen route of administration , i . e ., orally or parenterally , by intravenous , intramuscular , topical or subcutaneous routes , or by inhalation or insufflation . thus , the present compounds may be systemically administered , e . g ., orally , in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier . they may be enclosed in hard or soft shell gelatin capsules as powders , pellets or suspensions or may be compressed into tablets . for oral therapeutic administration , the active compound may be combined with one or more excipients and used in the form of ingestible tablets , buccal tablets , troches , capsules , elixirs , suspensions , syrups , wafers , and the like . such compositions and preparations should contain at least 0 . 1 % of active compound . the percentage of the compositions and preparations may , of course , be varied and may conveniently be between about 2 to about 60 % of the weight of a given unit dosage form . the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained . the tablets , troches , pills , capsules , and the like may also contain the following : binders such as gum tragacanth , acacia , corn starch or gelatin ; excipients such as dicalcium phosphate ; a disintegrating agent such as corn starch , potato starch , alginic acid and the like ; a lubricant such as magnesium stearate ; and a sweetening agent such as sucrose , fructose , lactose or aspartame or a flavoring agent such as peppermint , oil of wintergreen , or cherry flavoring may be added . when the unit dosage form is a capsule , it may contain , in addition to materials of the above type , a liquid carrier , such as a vegetable oil or a polyethylene glycol . various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form . for instance , tablets , pills , or capsules may be coated with gelatin , wax , shellac or sugar and the like . a syrup or elixir may contain the active compound , sucrose or fructose as a sweetening agent , methyl and propylparabens as preservatives , a dye and flavoring such as cherry or orange flavor . of course , any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non - toxic in the amounts employed . in addition , the active compound may be incorporated into sustained - release preparations and devices , such as patches , infusion pumps or implantable depots . the active compound may also be administered intravenously or intraperitoneally by infusion or injection . solutions of the active compound or its salts can be prepared in water , optionally mixed with a nontoxic surfactant . dispersions can also be prepared in glycerol , liquid polyethylene glycols , triacetin , and mixtures thereof and in oils . under ordinary conditions of storage and use , these preparations contain a preservative to prevent the growth of microorganisms . the pharmaceutical dosage forms suitable for injection , infusion or inhalation can include sterile aqueous solutions or dispersions . sterile powders can be prepared comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions , optionally encapsulated in liposomes . in all cases , the ultimate dosage form should be sterile , fluid and stable under the conditions of manufacture and storage . the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising , for example , water , ethanol , a polyol ( for example , glycerol , propylene glycol , liquid polyethylene glycols , and the like ), vegetable oils , nontoxic glyceryl esters , and suitable mixtures thereof . the proper fluidity can be maintained , for example , by the formation of liposomes , by the maintenance of the required particle size in the case of dispersions or by the use of surfactants . the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents , for example , parabens , chlorobutanol , phenol , sorbic acid , thimerosal , and the like . in many cases , it will be preferable to include isotonic agents , for example , sugars , buffers or sodium chloride . prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption , for example , aluminum monostearate , cellulose ethers , and gelatin . sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above , as required , followed by filter sterilization . in the case of sterile powders for the preparation of sterile injectable solutions , the preferred methods of preparation are vacuum drying and the freeze drying techniques , which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile - filtered solutions . for topical administration , the present compounds may be applied in pure form , i . e ., when they are liquids . however , it will generally be desirable to administer them to the skin as compositions or formulations , in combination with a dermatologically acceptable carrier , which may be a solid or a liquid . useful solid carriers include finely divided solids such as talc , clay , microcrystalline cellulose , silica , alumina and the like . useful liquid carriers include water , alcohols or glycols or water - alcohol / glycol blends , in which the present compounds can be dissolved or dispersed at effective levels , optionally with the aid of non - toxic surfactants . adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use . the resultant liquid compositions can be applied from absorbent pads , used to impregnate bandages and other dressings , or sprayed onto the affected area using pump - type or aerosol sprayers . thickeners such as synthetic polymers , fatty acids , fatty acid salts and esters , fatty alcohols , modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes , gels , ointments , soaps , and the like , for application directly to the skin of the user . examples of useful dermatological compositions which can be used to deliver the compounds of formula i to the skin are known to the art ; for example , see jacquet et al . ( u . s . pat . no . 4 , 608 , 392 ), geria ( u . s . pat . no . 4 , 992 , 478 ), smith et al . ( u . s . pat . no . 4 , 559 , 157 ) and wortzman ( u . s . pat . no . 4 , 820 , 508 ). useful dosages of the compounds of formula i can be determined by comparing their in vitro activity , and in vivo activity in animal models . methods for the extrapolation of effective dosages in mice , and other animals , to humans are known to the art ; for example , see u . s . pat . no . 4 , 938 , 949 . generally , the concentration of the compound ( s ) of formula i in a liquid composition , such as a lotion , will be from about 0 . 1 - 25 wt -%, preferably from about 0 . 5 - 10 wt -%. the concentration in a semi - solid or solid composition such as a gel or a powder will be about 0 . 1 - 5 wt -%, preferably about 0 . 5 - 2 . 5 wt -%. the amount of the compound , or an active salt or derivative thereof , required for use in treatment will vary not only with the particular salt selected but also with the route of administration , the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician . in general , however , a suitable dose will be in the range of from about 0 . 5 to about 100 mg / kg , e . g ., from about 10 to about 75 mg / kg of body weight per day , such as 3 to about 50 mg per kilogram body weight of the recipient per day , preferably in the range of 6 to 90 mg / kg / day , most preferably in the range of 15 to 60 mg / kg / day . the compound is conveniently administered in unit dosage form ; for example , containing 5 mg to as much as 1 - 3 g , conveniently 10 to 1000 mg , most conveniently , 50 to 500 mg of active ingredient per unit dosage form . ideally , the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0 . 5 to about 75 μm , preferably , about 1 to 50 μm , most preferably , about 2 to about 30 μm . this may be achieved , for example , by the intravenous injection of a 0 . 05 to 5 % solution of the active ingredient , optionally in saline . for example , as much as about 0 . 5 - 3 g of a compound of formula i can be dissolved in about 125 - 500 ml of an intravenous solution comprising , e . g ., 0 . 9 % nacl , and about 5 - 10 % glucose . such solutions can be infused over an extended period of up to several hours , optionally in conjunction with other anti - viral agents , antibiotics , etc . the active ingredient can also be orally administered as a bolus containing about 1 - 100 mg of the active ingredient . desirable blood levels may be maintained by continuous infusion to provide about 0 . 01 - 5 . 0 mg / kg / hr or by intermittent infusions containing about 0 . 4 - 15 mg / kg of the active ingredient ( s ). the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals , for example , as two , three , four or more sub - doses per day . the sub - dose itself may be further divided , e . g ., into a number of discrete loosely spaced administrations ; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye . the ability of a compound of the invention to act as an antiviral agent may be determined using pharmacological models which are well known to the art , or using tests described below . the following illustrate representative pharmaceutical dosage forms , containing a compound of formula i , for therapeutic or prophylactic use in humans . ( i ) tablet 1 mg / tablet procainamide 100 . 0 lactose 77 . 5 povidone 15 . 0 croscarmellose sodium 12 . 0 microcrystalline cellulose 92 . 5 magnesium stearate 3 . 0 300 . 0 the invention will be further described by reference to the following detailed examples , wherein aβ 1 - 42 peptide was purchased from american peptide co . ( sunnyvale , calif .). procaine , tetracaine , lidocaine , procainamide , the antioxidant tert - butyl - phenylnitrone ( pbn ), the n - methyl - d - aspartate ( nmda ) receptor antagonist (+)- m801 , and tetrodotoxine ( ttx ) were purchased from sigma ( st . louis , mo .). structures of procaine , tetracaine , lidocaine , procainamide sp015 , sp016 and sp017 are shown in fig1 . cell culture supplies were purchased from gibco ( grand island , n . y .) and cell culture plasticware was from corning ( corning , n . y .) and packard biosciences co . ( meriden , conn .). rna stat - 60 was from tel - test , inc . ( friendswood , tex .). taqman ® reverse transcription reagents , random hexamers , and sybr ® green pcr master mix were from applied biosystems ( foster city , calif .). the interbioscreen database of naturally occurring entities was screened for compounds containing the procaine structure using the isis software ( information systems , inc ., san leandro , calif .). acetic acid 7 - acetoxy - 3 -( 4 - benzoyl - piperazin - 1 - yl - methyl )- 5 - hydroxy - 4a , 8 - dimethyl - 2 - oxo - dodecahydro - azuleno [ 6 , 5 - b ] furan - 4 - yl ester ( sp015 ), acetic acid 5 - acetoxy - 3 -( 4 - benzoyl - piperazin - 1 - yl - methyl )- 4 - hydroxy - 4a , 8 - dimethyl - 2 - oxo - dodecahydro - azuleno [ 6 , 5 - b ] furan - 7 - yl ester ( sp016 ) and 3 -( 4 - benzoyl - piperazin - 1 - yl - methyl )- 6 , 6a - epoxy - 6 , 9 - dimethyl - 3a , 4 , 5 , 6 , 6a , 7 , 9a , 9b - octahydro - 3h - azuleno [ 4 , 5 - b ] furan - 2 - one ( sp017 ) compounds identified were purchased from interbioscreen ( moscow , russia ) ( fig1 ). pc12 cells ( rat pheochromocytoma ) ( atcc , manassas , va .) were cultured in rpmi 1640 without glutamine medium containing 10 % of bovine serum and 5 % of horse serum at 37 ° and 5 % co 2 . these cells respond reversibly to ngf by induction of the neuronal phenotype . pc12 cells were incubated for 24 hours in 96 - well plates ( 5 . 10 4 cells per well ) with increasing concentrations ( 1 , 10 and 100 μm ) of procaine , procainamide , lidocaine , tetracaine , sp015 , sp016 , sp017 or sp008 . aβ 1 - 42 was incubated overnight at 4 ° c . and then added to the cells at 0 . 1 , 1 or 10 μm final concentrations for a 24 hours time period . to study the role played by the nmda receptor in the aβ 1 - 42 - induced neurotoxicity , increasing concentrations of (+)- mk801 were added to the cell media immediately before aβ 1 - 42 cell viability was assessed 4 hours later using the mtt assay . to assess the effect of procaine and sp008 on the glutamate - induced excitotoxicity , pc12 cells were pre - treated with procaine or sp008 at 0 . 3 , 1 , 3 , 10 and 30 μm for 24 hours and then submitted to glutamate exposure for another 24 hour time period . cell viability was subsequently assessed using the mtt assay . to assess the role of sodium channels in aβ 1 - 42 - induced neurotoxicity , pc12 cells were incubated for 4 hours with the sodium - channel blocker ttx at 3 , 30 or 300 μm followed by addition of aβ 1 - 42 cell viability was assessed by mtt 24 hours later . the involvement of the oxidative stress in the toxicity of aβ 1 - 42 was assessed by incubating the pc12 in the presence of 10 , 100 or 500 μm pbn for 24 hours . aβ 1 - 42 was then added to the incubation media . cell viability was assessed by mtt 24 hours later . the cellular toxicity of aβ was assessed using the 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyl tetrazolium bromide ( mtt ) assay ( trevigen , gaithersburg , md .) as previously described [ lecanu et al . ( 2004 ) steroids , 69 : 1 - 16 .]. briefly , 10 μl of the mtt solution were added to the cells cultured in 100 μl of medium . after an incubation period of 4 hours in the same conditions as above , 100 μl of detergent were added and cells incubated overnight at 37 ° c . the blue coloration was quantified at 600 nm and 690 nm using the victor spectrophotometer ( egg - wallac , gaithersburg , md .). the effect of aβ 1 - 42 was expressed as ( do 600 - do 690 ). to compare the protective effect of the compounds tested , the decrease of mtt signal observed with aβ 1 - 42 was considered to be the 100 % inhibition of the nadph diaphorase activity and the effect of the compounds tested is shown as an increase or decrease of this percentage . atp concentrations were measured using the atplite - m ™ assay ( packard biosciences co . ), as previously described [ lecanu et al ., cited above ]. in brief , cells were cultured on black 96 - well viewplate ™ and the atp concentrations measured on a topcount nxt ™ counter ( packard biosciences co .) according to the manufacturer recommendations . the effect of aβ 1 - 42 was expressed in arbitrary units . to compare the potential protective effect of the compounds tested on atp recovery , the decrease of atp concentration induced by aβ 1 - 42 was considered to be 100 % reduction and the effects of the compounds tested are shown as changes of this percentage . oxidative stress was assessed by measuring the free radical production using the fluorescent probe di - hydroxy di - chlorofluorescein diacetate ( 2 , 7 - dcf ) ( molecular probes , eugene , oreg . ), as previously described [ lecanu et al ., cited above ]. for these experiments , cells were cultured in polylysine coated microplates . cells were washed once with rpmi 1640 and medium was then replaced by 100 μl rpmi 1640 . cells were incubated 45 minutes at room temperature in the dark with 100 μl of 2 , 7 - dcf 50 μm and the fluorescence ( excitation λ = 485 nm , emission λ = 535 nm ) was measured using the victor multilabel counter ( egg - wallac , gaithersburg , md .). radioligand binding studies were performed using human recombinant sigma - 1 receptor expressed in jurkat cells . increasing concentrations of procaine ranging from 3 . 0e - 10 to 1 . 0e - 05 m were incubated for 120 minutes at 22 ° c . in presence of the specific sigma - 1 receptor ligand [ 3 h ]-(+)- pentazocine at 8 nm to determine procaine ic50 and hill value nh . pc12 cells cultured in 6 - well plates for 18 hours were treated with increasing concentrations of procaine for the indicated time period . after treatment , cells were exposed to of aβ 1 - 42 1 μm for 24 hours . at the end of the incubation , total cell rna was extracted using rnastat - 60 ( tel - test , inc ., friendswood , tex .) according to the manufacturer &# 39 ; s instructions . hmg - coa reductase mrna was quantified by q - pcr using the abi prism 7700 sequence detection system ( perkin - elmer / applied biosystems , foster , city , calif .). rt reaction was performed using taqman ® reverse transcription reagents with 1 μg total rna and random hexamers as primers for each reaction , as previously described [ xu et al . ( 2003 ) j . pharmacol . ther ., 307 : 1148 - 57 ]. for quantifying rat hmg - coa reductase mrna with q - pcr , the primers were designed according to genbank accession number bc 019782 using pe / ab primer express software , which is specifically designed for the selection of primers and probes . the forward primer was 5 ′- gac tgt ggt ttg tga agc tgt cat - 3 ′ ( 24 nucleotides ) and reverse primer was 5 ′- aat act tct ctc acc acc ttg gct - 3 ′ ( 24 nucleotides ), respectively . the primers were synthesized by biosynthesis , inc . ( lewisville , tex .). reactions were performed in a reaction mixture consisting of a 20 μl solution containing 10 μl sybr ® green pcr master mix and 1 μl primers mix ( 5 μm each ) with 2 μl cdna . the cycling conditions were : 15 seconds at 95 ° c . and 1 minute at 60 ° c . for 40 cycles following an initial step of 2 minutes at 50 ° c . and 10 minutes at 95 ° c . amplitaq gold polymerase was activated at 95 ° c . for 10 minutes . the 18s rna was amplified at the same time and used as an internal control . to exclude the contamination of unspecific pcr products such as primer dimmers , a melting curve analysis was applied to all final pcr products after the cycling protocol . also , pcr reactions without the rt reaction were performed for each sample in order to exclude genomic dna contamination . the pcr products were collected and run on a 3 % ( w / v ) agarose / tae gel to confirm the product size . the threshold cycle ( ct ) values for 18s rna and samples were calculated using the pe / ab computer software . ct was determined at the most exponential phase of the reaction . relative transcript levels were calculated as x = 2δδct , in which δδct = δe − δc , and δe = ct experiment − ct 18s , δc − ct control − ct 18s . data are expressed as mean ± sd . data obtained were assessed between experimental groups by a one - way anova and dunnett &# 39 ; s test was used for comparison . a difference was considered significant when p & lt ; 0 . 05 . aβ 1 - 42 neurotoxicity assessed by mtt assay , atp measurement and free radical production in pc12 cells ( fig2 ) aβ 1 - 42 induces a dose - dependent decrease of pc12 cell viability ( p & lt ; 0 . 001 ) ( fig2 a ) and of the intra - cellular atp concentrations ( p & lt ; 0 . 001 ) ( fig2 b ). a dose - dependent relationship is also observed on the free radical production as aβ 1 - 42 at 1 and 10 μm concentrations induced a significant increase of the oxidative stress ( p & lt ; 0 . 01 and p & lt ; 0 . 001 respectively ) ( fig2 c ). effect of the procaine and the procaine derivatives on the cell viability assessed by mtt as shown on table 1 , procaine displays an important protective effect against 0 . 1 and 1 μm aβ 1 - 42 induced toxicity assessed using the mtt assay . treatment with 1 and 10 μm procaine resulted in a reduction of the nadph diaphorase inhibition induced by aβ 1 - 42 of at least 30 % ( p & lt ; 0 . 01 ); at higher concentrations procaine was less effective . lidocaine reduced significantly the nadph diaphorase inhibition when used at 1 μm even against the highest concentration of aβ 1 - 42 ( 71 . 2 ± 16 . 6 % compared to the control 100 . 0 ± 5 . 3 %, n = 6 , p & lt ; 0 . 01 ). lidocaine at 10 μm provided a protection equivalent to that observed with 1 μm except against the lowest dose of aβ 1 - 42 ; again the concentration of 100 μm lidocaine was less efficacious than the 1 and 10 μm concentrations and without effect against 10 μm aβ 1 - 42 . the three concentrations of tetracaine protected against 10 μm aβ 1 - 42 with the strongest effect observed by 100 μm tetracaine ( 39 . 6 ± 16 . 6 % compared to control 100 . 0 ± 5 . 3 %, p & lt ; 0 . 001 , n = 6 ). only this tetracaine concentration was able to reduced the nadph diaphorase inhibition induced by aβ 1 - 42 0 . 1 and 1 μm with respectively 60 . 1 ± 8 . 2 % versus 100 . 0 ± 8 . 8 % for the control ( p & lt ; 0 . 01 , n = 6 ) and 43 . 7 ± 7 . 6 % versus 100 . 0 ± 6 . 6 % for the control ( p & lt ; 0 . 001 , n = 6 ). the three concentrations of procainamide used dramatically reduced the nadph diaphorase inhibition induced by aβ 1 - 42 except the 100 μm concentration against 0 . 1 μm aβ 1 - 42 . the highest level of neuroprotection was observed with 10 μm procainamide and was equivalent to the result obtained with 100 μm tetracaine with respectively 68 . 0 ± 11 . 6 % versus 100 . 0 ± 8 . 8 % for the control ( p & lt ; 0 . 01 , n = 6 ), 49 . 3 ± 8 . 0 % versus 100 . 0 ± 6 . 6 % for the control ( p & lt ; 0 . 001 , n = 6 ) and 51 . 4 ± 16 . 7 % versus 100 . 0 ± 5 . 3 % for the control ( p & lt ; 0 . 001 , n = 6 ). the identified naturally occurring procaine derivatives also displayed neuroprotective properties against aβ 1 - 42 neurotoxicity in pc12 cells but at concentrations different to those reported above for procaine . sp015 protected only at 1 and 10 μm concentrations against the highest concentration of aβ 1 - 42 , whereas sp016 had no protective activity . sp017 at 1 μm reduced the diaphorase inhibition induced by aβ 1 - 42 but the best effect was observed with sp017 10 μm which was able to protect against the three concentrations of aβ 1 - 42 tested ( 70 . 1 ± 21 . 9 % versus 100 . 0 ± 8 . 8 % for the control , p & lt ; 0 . 05 , n = 6 ; 71 . 9 ± 14 . 6 % versus 100 . 0 ± 6 . 6 % for the control , p & lt ; 0 . 01 , n = 6 , and 69 . 4 ± 21 . 7 % versus 100 . 0 ± 5 . 3 % for the control , p & lt ; 0 . 05 , n = 6 . sp017 at 100 μm potentiated the toxic effect of aβ 1 - 42 suggesting a probable toxicity . effect of the procaine and procaine derivatives on aβ 1 - 42 - induced atp decrease as shown in table 2 , procaine protected against the 0 . 1 μm aβ 1 - 42 - induced depletion of atp concentrations in a dose - dependent manner , whereas its protective effect was less consistent against 1 μm aβ 1 - 42 and did not occur against 10 μm aβ 1 - 42 . lidocaine tested at 1 and 10 μm restored atp concentrations in pc12 cells exposed to 0 . 1 and 1 μm aβ 1 - 42 ( p & lt ; 0 . 01 , n = 6 ) with the most important effect observed against 0 . 1 μm aβ 1 - 42 . lidocaine tested at the concentration of 100 μm exerted a protective effect against all concentrations of aβ 1 - 42 , although this effect was statistically significant only against 10 μm aβ 1 - 42 with 100 . 0 ± 23 . 4 % ( p & lt ; 0 . 05 , n = 6 ). the three concentrations of tetracaine and procainamide tested significantly prevented the aβ 1 - 42 - induced decrease of intracellular atp levels . among the natural derivatives of procaine , sp015 at 1 μm and sp017 at 1 and 10 μm concentrations were able to reverse the effect of aβ 1 - 42 on atp . effect of the nmda antagonist (+)- mk801 on aβ 1 - 42 - induced neurotoxicity procaine and others local anesthetics have been shown to inhibit the nmda receptor and an over - activation of the nmda receptor has been demonstrated to contribute to aβ 1 - 42 neurotoxicity . therefore , in order to assess if a neuroprotective effect of procaine could be due to the blockade of the nmda neurotransmission , it was determined if a nmda hyperactivity occurs in this experiment . this was studied by using (+)- mk801 , a non - competitive inhibitor of nmda receptor , on aβ 1 - 42 neurotoxicity . (+)- mk801 lessens in a dose - dependent manner pc12 cell viability decrease induced by aβ 1 - 42 ( fig3 ). (+)- mk801 used at 25 μm concentrations protected pc12 cells against 0 . 1 and 1 μm aβ 1 - 42 - induced toxicity ( p & lt ; 0 . 05 ). (+)- mk801 used at 100 μm concentrations provided the most significant neuroprotective effect against all concentrations of aβ 1 - 42 tested ( p & lt ; 0 . 001 ). displacement study of the [ 3 h ](+) pentazocine by procaine on sigma - 1 receptor because the sigma - 1 receptor regulates or preserves important physiological functions or processes which are altered in ad , like calcium homeostasis , memory , mood and mitochondria functions , it is of interest to test the ability of procaine to bind this receptor . in order to do it , the displacement of the specific sigma - 1 ligand pentazocine by procaine was measured . procaine displaced the [ 3 h ](+) pentazocine from its binding site on the sigma - 1 receptor expressed in jurkat cells with an ic50 of 4 . 3 μm . the hill coefficient ( nh = 1 . 0 ) revealed a single binding site for procaine on the sigma - 1 receptor . glutamate 100 μm dramatically reduced pc12 cell viability ( p & lt ; 0 . 001 , n = 6 ; fig5 ). procaine prevented the glutamate - induced neurotoxicity in a biphasic manner . two maximum effects were observed at 0 . 3 and 10 μm ( p & lt ; 0 . 001 compared to control , n = 6 ). the sp008 effect was also biphasic reaching a protective peak at 3 μm ( p & lt ; 0 . 001 compared to control , n = 6 ) followed by a decline in its neuroprotective property in the presence of at higher concentrations of glutamate . the neuroprotective effect of sp008 was more important than that of procaine effect at the same concentration ( p & lt ; 0 . 001 , n = 6 ). effect of the procaine and procaine derivatives on aβ 1 - 42 - induced free radical production as shown in fig2 c aβ 1 - 42 - induced in a dose - dependent manner the production of free radicals in pc12 cells . procaine ( fig4 a ), procainamide ( fig4 b ), lidocaine ( fig4 c ) and tetracaine ( fig4 d ) exhibited a trend to reduce the aβ 1 - 42 - induced free radical production . this effect was statistically significant in the presence of 10 μm procaine incubated with 1 μm aβ 1 - 42 ( p & lt ; 0 . 05 , n = 6 ), 1 μm procaine when incubated with 0 . 1 μm aβ 1 - 42 ( p & lt ; 0 . 05 , n = 6 ), 100 μm tetracaine when incubated with 1 μm aβ 1 - 42 ( p & lt ; 0 . 05 , n = 6 ) and 1 and 10 μm procainamide when incubated with 0 . 1 and 1 μm aβ 1 - 42 ( p & lt ; 0 . 01 , n = 6 ). sp015 , sp016 and sp017 compounds did not affect the aβ 1 - 42 - induced oxidative stress . on the contrary , these compounds amplified the aβ 1 - 42 - induced free radicals production . aβ 1 - 42 ( 1 μm ) induced a significant increase of hmg - coa mrna synthesis compared to the control pc12 cells ( 1 . 48 ± 0 . 17 times the control level , p & lt ; 0 . 05 ; fig6 ). procaine decreased in a dose - dependent manner the level of mrna induced by aβ 1 - 42 but did not affect the basal level of hmg - coa reductase mrna measured in control pc12 . during the past decades , improving the cholinergic network dysfunction associated with ad has been the main focus of the scientific community . this led to the creation of the therapeutic class of the acetylcholinesterase inhibitors ( achei ) with the tacrine as the class leader . despite promising clinical data , the beneficial effects of tacrine were modest and the new generation of achei , represented by galantamine and donezepil , did not improve the delay of symptom onset compared to tacrine . this short 1 - 2 years delay , although priceless for the patients and their relatives , is probably due to the progressive degeneration of the cholinergic neurons and is a limitation of the use of achel . even though the improvement of the cholinergic transmission of the patients suffering from ad is relevant and necessary , it is certainly not sufficient to stop or reverse the progression of the disease . since , no major advance has been made in ad drug development , even though memantine , an antagonist of the glutamatergic nmda - subtype receptor was recently approved to be released in the us market . the present invention provides a new class of compounds derived from the homologous domain of a series of natural compounds which were obtained by screening a database using procaine as a starting point . these molecules can protect rat pheochromocytoma pc12 cells against aβ 1 - 42 neurotoxicity . the adrenal hormone cortisol was described to worsen the ad evolution by enhancing the neuronal death , altering the mood and inducing depression and xu et al recently reported that a procaine - based pharmaceutical preparation reduced the stress - induced hypercorticosteronism in rat [ j . pharmacol . exp . ther ., 307 : 1148 ( 2003 )], presenting therefore procaine as an interesting approach to treat ad . however , the quick degradation of procaine into para - aminobenzoic acid and diethylaminoethanol renders it difficult to use therapeutically for ad . sp015 , sp016 and sp017 were obtained by screening natural compounds database using procaine as a sub - structure ( fig1 ) and they originate from plants of the asteraceae family , inula britanica and artemisia glabella . strikingly , plants from artemisia genus have been used traditionally as restoratives of lost or declining mental functions [ wake et al ., ( 2000 ) j . ethnopharmacol . 69 : 105 - 14 ]. procaine was able to restore partially the decrease of atp production induced by aβ 1 - 42 suggesting an activity on the mitochondrial respiratory chain . among the screened natural compounds , sp017 showed the highest protective effect on the mitochondrial function , as evidenced by the changes seen in mitochondrial diaphorase activity , with efficacy range of 30 - 70 % of inhibition of aβ 1 - 42 toxicity . interestingly , despite the important chemical similarity between sp015 and sp016 , sp016 displayed a significant effect only against low aβ 1 - 42 concentrations ( 0 . 1 μm ) when administered at 1 μm whereas 1 μm sp015 offered an important protection even against the highest aβ 1 - 42 concentration examined . surprisingly , the effect of these different compounds on pc12 viability after aβ 1 - 42 exposure did not completely match the effect observed on the restoration of atp content . in particular , sp015 displayed a neuroprotective effect at 1 and 10 μm only against 10 μm aβ 1 - 42 while no effect was observed with sp016 . this apparent discrepancy suggests that the preservation of the intracellular atp stock is not the only mechanism by which the procaine and procaine derivatives exert their neuroprotective properties . the glutamatergic network is also targeted by the β - amyloid peptides since aβ 1 - 40 [ wu et al ., neuroreport , 6 , 2409 ( 1995 )] and aβ 25 - 35 [ mogensen et al ., neuroreport , 9 , 1553 ( 1998 )] have been described to selectively augment nmda - receptor - mediated , but not ampa , synaptic transmission in rat hippocampus . however , different results indicated that the non - nmda receptor - evoked calcium inward current contributed to the neurotoxicity displayed by aβ 1 - 42 on differenciated human nt2 - n neurons [ blanchard et al ., brain res ., 21 , 776 ( 1 - 2 ): 40 ( 1997 )]. thus , even though no data are available regarding an inhibitory effect of procaine on the ampa / kainate receptors , the possibility that such a mechanism participated in the observed neuroprotection remains to be established . interestingly , the nmda receptor antagonist mk - 801 protected cholinergic nucleus basalis neurons and striatal neurons from amyloid peptide neurotoxicity in vivo [ parks et al ., j . neurochem ., 76 , 1050 ( 2001 ); harkany et al ., eur . j . neurosci ., 12 , 2735 ( 1999 )] and in vitro on neuroblastoma cells , whereas ap - 5 , which binds specifically the glutamate site , did not [ le et al ., brain res ., 686 , 49 ( 1995 )]. these results led these authors to conclude that amyloid peptides might act more by stabilizing the opening state of the nmda - associated calcium channel after inserting into the plasma membrane rather than by directly binding the glutamate site . strikingly , the mk - 801 reduced in a dose - dependent manner the neurotoxicity induced by aβ 1 - 42 suggesting , therefore , the involvement of an over - stimulation of the nmda receptors in the neurotoxicity discussed herein . moreover , procaine reduced the glutamate - induced excitotoxicity on the pc12 cells , indicating that the inhibition of the nmda - induced calcium inward current might account for the protective effect provided by the compounds of the invention . this data is reinforced by recent findings reporting that local anesthetic agents inhibit nmda receptor channel in mouse ca1 pyramidal neurons [ nishizawa et al ., anesth . anaig ., 94 325 ( 2002 )] and in xenopus oocytes [ sugimoto et al ., brit . j . pharmacol ., 138 , 876 ( 2003 )]. the mechanism by which the local anesthetics inhibit the nmda receptor depends on their respective pka . with a pka of 8 . 9 , procaine is the more ionized at physiological state and therefore , is probably more prone to bind a site located inside the calcium channel and to act in a voltage - dependent fashion . on the other hand , lidocaine has a pka of 7 . 9 , suggesting that this molecule exists essentially as a non - ionized lipophilic form at physiological ph and acts by inserting the plasma membrane and by allosterically modifying the nmda receptor . with an intermediate pka of 8 . 5 , tetracaine is expected to inhibit the nmda receptor by both mechanisms , which might therefore explain the highest efficacy of this compound in protecting pc12 cells against aβ 1 - 42 neurotoxicity . such a mechanism of action might have accounted for the neuroprotective effect observed with the natural compounds sp015 and sp017 since they have been selected from databases using procaine as a substructure . interestingly , an over - activation of the rat hippocampus nmda receptors by aβ 1 - 42 has been described to affect the long - term depression and , in turn , the long - term potentiation [ kim et al ., j . neurosci ., 21 , 1327 ( 2001 )], the two main forms of synaptic plasticity in the brain . this deleterious pathway has been proposed to contribute to the memory processes hampered in ad . procaine further exhibits the ability to bind the sigma - 1 ( σ1 ) receptor with an ic 50 of 4 . 3 μm and a hill coefficient of 1 . 0 , indicating the presence of an unique binding site . several σ1 - receptor agonists have been described to reverse in a dose - dependent manner the scopolamine - induced amnesia in rats . interestingly , one of them , the sa4503 , enhanced the ach release in the hippocampus of rat brain slices [ horan et al ., synapse , 46 , 1 ( 2002 )] and in vivo [ kobayashi et al ., j . pharmacol . exp . ther ., 279 , 106 ( 1996 )], suggesting that the anti - amnesic effect could be due in part to the activation of the cholinergic pathway . in addition , the effect of the binding on the r 1 - receptor on the ach release seems to be much more pronounced in the hippocampus compared to tacrine [ kobayashi et al ., j . pharmacol . exp . ther ., 279 , 106 ( 1996 )]. in addition , igmesine , a v 1 - receptor agonist , was recently demonstrated to exert an antidepressant activity in mice intracerebroventrically injected with the amyloid fragment aβ25 - 35 [ urani et al ., behav . brain res ., 134 , 239 ( 2002 )], probably via a modification of the monoaminergic system [ akunne et al ., neuropharmacol ., 41 , 138 ( 2001 )]. in addition , recent data reported that σ1 - receptor ligands protect neuronal cells against transient cerebral ischemia in rat [ goyagi et al ., anesth . analg ., 96 , 532 ( 2003 )], prevented the hypoxia - induced atp depletion in astrocytes [ klouz et al ., febs lett ., 553 157 ( 2003 )] and facilitated neurite sprouting induced by nerve growth factor in pc12 cells [ takebayashi et al ., j . pharm . exp . ther ., 303 , 1227 ( 2002 )]. procaine bound selectively the a i - receptor compared to the σ2 - receptor ( ic50 & gt ; 10 μm ) and therefore it might be devoid of the pro - apoptotic properties and cytotoxic effect described for the σ2 - receptor agonists . procaine was recently demonstrated to downregulate the stress - induced cortisol increase in vivo in rats and in vitro in dbcamp - stimulated leydig cells [ xu et al ., j . pharmacol . exp . ther ., 307 , 1148 ( 2003 )]. the data reported indicated that the decrease of the cortisol production by the adrenal cortical cells was due to a decrease in the expression of cholesterol synthesis rate limiting enzyme hmg - coa reductase mrna and correlates with the restoration of cell viability . the effect of procaine on hmg - coa mrna levels in pc12 cells “ stressed ” by aβ 1 - 42 exposure reported herein is equivalent to that previously reported by xu et al . for adrenal cells “ stressed ” by camp . interestingly , the ability of aβ 1 - 42 to modulate the hmg - coa activity through an increase of the expression of its mrna is complementary to recent findings on the physiological function of the beta - amyloid peptide in the control of neuronal cholesterol levels and transport [ yao et al ., brain res ., 847 , 203 ( 2002 ); wood and igbavboa , pharmopsychiatry , 36 ( s2 ), 3144 - 148 ( 2003 )]. however , it is very unlikely that any reduction of corticosteroid synthesis accounts for the protective effect of procaine against aβ 1 - 42 , as pc12 pheochromocytoma cells do not produce steroids . it is more likely that the dose - dependent reduction of hmg - coa mrna expression by procaine results , first , in a decrease of the cholesterol production with , as a direct consequence , a modification of the membrane fluidity and an alteration of aβ 1 - 42 trafficking through the cell membrane . these modifications might therefore render the cell less sensitive to aβ 1 - 42 - induced neurotoxicity . in addition , the reduction of cholesterol synthesis has been shown to reduce app cleavage and beta - amyloid peptide production by reducing γ - secretase activity . all publications , patents , and patent documents are incorporated by reference herein , as though individually incorporated by reference . the invention has been described with reference to various specific and preferred embodiments and techniques . however , it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention .
the invention provides a therapeutic method for treating at least one symptom of a neurological disorder or disease such as alzheimer &# 39 ; s disease in a mammal , such as a human , wherein the toxicity of a pathogen of β amyloid peptide and / or glutamate in mammalian cells is implicated and inhibition of the subsequently - induced pathological pathways is desired comprising administering to a mammal in need of such therapy , an effective amount of an n - arylamide or an benzamide , including pharmaceutically acceptable salts thereof .