title: Pharmacological characterization of (S)-(2)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine HCl (SIB-1508Y, Altinicline), a novel nicotinic acetylcholine receptor agonist.
abstract: (S)-(2)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine HCl (SIB-1508Y, Altinicline), is a subtype-selective neuronal nicotinic acetylcholine receptor (nAChR) agonist. In rodents, SIB-1508Y exhibited antidepressant activity, reversed age-related decrements in vigilance, and improved motor and cognitive function in primate models of Parkinson's disease. The goal of the study was to explore neurochemical effects of SIB-1508Y and its isomer, SIB-1680WD. In vitro, SIB-1508Y increased dopamine (DA) release from slices of rat striatum, nucleus accumbens (NAc), olfactory tubercles (OT) and prefrontal cortices (PFC) in a concentration-dependent manner. Relative to its robust effects on DA release from various brain regions, SIB-1508Y was minimally effective at increasing NE release from hippocampus or PFC, and 5-HT release from PFC. SIB-1680WD was less potent and efficacious than SIB-1508Y, but did not act as a partial agonist. Subcutaneous injection of SIB-1508Y (10 mg/kg) increased striatal DA release and this release was sensitive to blockade by the non-competitive nAChR antagonist, mecamylamine (Mec). SIB-1508Y also increased hippocampal ACh release selectively without affecting striatal ACh release. Hippocampal ACh release evoked by SIB-1508Y was attenuated by nAChR antagonists Mec and Dihydro-beta-erythroidine (DHbetaE), and also by the DA D1 receptor antagonist, SCH-23390. These results are consistent with previously established pharmacology of nAChR regulation of hippocampal ACh release. Repeated administration of SIB-1508Y did not result in an enhanced striatal DA release or hippocampal ACh release. In summary, the abilities of SIB-1508Y to release multiple neurotransmitters in distinct brain regions may contribute to its behavioral profile.
authors.affiliation: Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA. trao@kalypsys.com
authors.forename: Tadimeti S
authors.initials: TS
authors.lastname: Rao
authors.forename: Pamala B
authors.initials: PB
authors.lastname: Adams
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Correa
authors.forename: Emily M
authors.initials: EM
authors.lastname: Santori
authors.forename: Aida I
authors.initials: AI
authors.lastname: Sacaan
authors.forename: Richard T
authors.initials: RT
authors.lastname: Reid
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013238:Stereotaxic Techniques
chemical_list: D018377:Neurotransmitter Agents; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; D000109:Acetylcholine; C100989:altinicline maleate; D004298:Dopamine; D009638:Norepinephrine