Cognitive disorders have many components including forgetfulness, confusion, memory loss, attentional deficits, and deficits in visual perception. Some of the symptoms of cognitive disorders are associated with decreased levels of the neurotransmitter, acetylcholine. Neurological illnesses related to cholinergic deficiency include presenile dementia and senile dementia of the Alzheimer's type (SDAT), Parkinson's disease, Downe's Syndrome and dementia pugilistica.
The "cholinergic hypothesis" R. T. Bartus, et al., Science, 217, 408-417 (Jul. 30, 1982)! suggests that memory loss due to decreased levels of acetylcholine can be ameliorated by correcting the levels of acetylcholine in the brain using an acetylcholine releasing agent, an acetylcholine esterase inhibitor, or by using a drug which mimics acetylcholine (cholinomimetic). Marketing of the acetylcholine esterase inhibitor, tacrine, has demonstrated that improvement in memory can be shown in patients with mild to moderate Alzheimer's Disease M. Williams, Curr. Opin. Invest. Drugs, 2(5), 541-544 (May 1993)!. The utility of this drug is limited, however, because of adverse side effects especially at the higher doses where it is most effective. Clinical studies using the natural alkaloid, arecoline, a cholinergic agonist, have also demonstrated memory improvement in patients with mild to moderate Alzheimer's Disease. Because of the short half-life of arecoline, the clinical study was done using continuous infusion of the drug over a 2 week period. In addition, a peripheral muscarinic antagonist, N-methylscopolamine, was also administered during the study to prevent potential autonomic side effects. T. T. Soncrant et al., Psychopharmacology, 112, 421-427 (1993)!.
Cholinergic receptors which bind to and are activated by the alkaloid, muscarine, are called muscarinic receptors. Three pharmacologically defined subtypes of muscarinic receptors have been identified. They are referred to as M1, M2, and M3 based upon their affinity for the M1 antagonist, pirenzepine, the M2 antagonist, AFDX-116, and the M3 antagonist, 4- (diphenylacetyl)oxy!-1,1-dimethylpiperidinium iodide (4-DAMP). Five different human muscarinic receptors have been cloned. The Hm1 (human m1) receptor is found primarily in the frontal cortex. T. I. Bonner, Trends in Pharmacological Sciences, supplement, Jul. 20-27 (1989) p11-15, !. Activation of the ml receptor results in an increase in phosphoinsoitide hydrolysis (PI turnover). K. Fukuda, et al., Ibid,. p. 4-10!.
EP-307-142-A discloses a group of azacyclic thiadiazole derivatives as useful central acetylcholine agonists and analgesics.
USPTO Backgrounds
USPTO Backgrounds