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: Tadimeti S Rao, Pamala B Adams, Lucia D Correa, Emily M Santori, Aida I Sacaan, Richard T Reid, Nicholas D P Cosford
• Journal: Brain research (Brain Res) Vol. 1234 Pg. 16-24 (Oct 09 2008) ISSN: 0006-8993 [Print] Netherlands
• PMID: 18692487 (Publication Type: Journal Article)

Chemical References

• Neurotransmitter Agents
• Nicotinic Agonists
• Pyridines
• Pyrrolidines
• Receptors, Nicotinic
• Acetylcholine
• altinicline maleate
• Dopamine
• Norepinephrine

Topics

• Acetylcholine (metabolism)
• Animals
• Brain Chemistry (drug effects)
• Chromatography, High Pressure Liquid
• Dopamine (metabolism)
• Dose-Response Relationship, Drug
• Hippocampus (drug effects, metabolism)
• Injections, Subcutaneous
• Male
• Microdialysis
• Neostriatum (drug effects, metabolism)
• Neurotransmitter Agents (metabolism)
• Nicotinic Agonists (administration & dosage, pharmacology)
• Norepinephrine (metabolism)
• Pyridines (administration & dosage, pharmacology)
• Pyrrolidines (administration & dosage, pharmacology)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Receptors, Nicotinic (drug effects)
• Stereotaxic Techniques