The mammalian neurokinins comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems. The three principal neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB).
There are also N-terminally extended forms of at least NKA. At least three receptor types are known for the three principal neurokinins. Based upon their relative selectivities favoring the neurokinin agonists SP, NKA and NKB, the receptors are classified as neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3) receptors, respectively.
It is now recognized that anxiety, stress, and depression are interrelated conditions (File S E Pharmacol, Biochem & Behavior 54/1:3-12, 1996). Moreover, these complex emotional states cannot be due simply to defects in a single neurotransmitter although 5-HT has been ascribed a principal role (Graeff et al., Pharmacol, Biochem & Behavior 54/1: 129-141, 1996). Substance P (SP) was one of the first neuropeptides to be identified in mammalian brain and it is now accepted that all three tachykinins are found within the CNS (Iversen L L J Psychopharmacol 3/1: 1-6, 1989), particularly in the striatonigral neurons, hypothalamus and limbic forebrain (ibid). NK1 and NK3 receptors have been identified in the brain as well (Beaujouan et al., Neurosci. 18: 857-875, 1986). Controversy has existed regarding the presence of the NK2 receptor in brain, although recent evidence shows receptor localization in at least the septal region (Steinberg et al., Eur J Neurosci 10/7:2337-45 1998).
Pharmacological evidence supporting a role for either NK1 or NK2 receptors in anxiety disorders has been accumulating from assorted animal behavioral tests (for examples, see Table 1). Animal models of depression, however, have been used rarely to define the potential utility of NK receptor antagonists. SP stimulates the turnover of other neurotransmitters involved in depression, i.e., 5-HT in the raphe nucleus, an area thought to be linked to depressive phenomena (Forchetti et al., J. Neurochem. 38: 1336-1341, 1982). When injected centrally to nuclei responsible for control of emotion and stress, SP evokes a hemodynamic pressor response bridging this peptide to stress induced hypertension (Ku et al., Peptides; 19/4:677-82, 1998). Moreover, rises in both heart rate and mean arterial blood pressure evoked by physical stress can be blocked in rodents by centrally administered NK1 receptor antagonists (Culman et al., J Pharmacol Exp Ther 280/1:238-46, 1997).
TABLE 1Neurokinin receptor antagonist activity in behavioraltests of anxiety/depression.Cpd (ReceptorAuthortype)Behavioral TestOutcomeTeixeira et al.,NK1 agonists &Elevatedagonists -Eur J PharmacolFK888 (NK1)plus-mazeanxiogenic5; 311(1): 7-14,SR48968 (NK2)antagonists -1996.anxiolyticFile Pharm Bio BCGP 49823Socialanxiolytic58(3): 747-752,(NK1)interaction1997.Vassout et alCGP 49823SocialanxiolyticNeuropeptides(NK1)interaction testinactive26/S1: 38, 1994.Elevatedantidepressantplus-maze(only atForced swim test30 mg/kg bid)(depressionmodel)Stratton et al.,GR100679Light-dark boxanxiolyticEur. J.(NK2)Pharmacol. 250:SR48968 (NK2)R11-12, 1993.Walsh et al.,GR159897Light-dark boxanxiolyticPsycho-(NK2)Marmoset humananxiolyticpharmacologySR48968 (NK2)intruder121: 186-191,1995.
USPTO Backgrounds
USPTO Backgrounds