(S)-(−)-5-Ethynyl-3-(1-methyl-2-pyrroli- dinyl)pyridine Maleate (SIB-1508Y):  A Novel Anti-Parkinsonian Agent with Selectivity for Neuronal Nicotinic Acetylcholine Receptors

Journal of Medicinal Chemistry
1996.0

Abstract

The selective modulation of neuronal receptor subtypes has considerable potential for disease treatment with minimal adverse effects, and the importance of nicotinic acetylcholine receptors (NAChRs) in Alzheimer's disease (AD) and Parkinson's disease (PD) is well established. This study reports the synthesis and pharmacological evaluation of (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate [(S)-2, SIB-1508Y], a novel agonist of human neuronal NAChRs. Structure-activity studies starting from nicotine led to the preparation of 5-substituted analogues; palladium-catalyzed cross-coupling and chiral auxiliary-mediated resolution (using CBZ-D-proline and tartrate salts) yielded enantiomerically pure (S)-2 (>99% ee). Pharmacological characterization included binding assays ([3H]-nicotine vs [3H]-quinuclidinyl benzylate in rat cortical membranes), in vitro dopamine release from rat striatal slices, electrophysiological recordings in Xenopus oocytes expressing recombinant human NAChR subtypes (α2β4, α3β4, α4β2, α4β4, etc.), calcium imaging in cell lines stably expressing these subtypes, and evaluation in a PD rat model (unilateral nigrostriatal 6-hydroxydopamine lesions, measuring ipsilateral rotations). Key results: (S)-2 was the more active enantiomer, exhibiting higher affinity for [3H]-nicotine binding sites (IC50 3 nM vs 75 nM for (R)-2) and greater efficacy in dopamine release (163% of nicotine's response). It selectively activated specific NAChR subtypes (e.g., α2β4, α4β2) with minimal activity at the α7 subtype (unlike nicotine, which potently activates α3β4 and α7). In the rat model, (S)-2 (25 mg/kg, subcutaneous) induced a significant increase in ipsilateral rotations with minimal adverse side effects, outperforming nicotine. Conclusion: (S)-2 is a promising candidate for preclinical development for PD, and functional assays using recombinant NAChR-expressing cell lines provide a powerful tool for identifying subtype-selective NAChR agonists.

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