ABSTRACT
[Structure: see text] The development of a concise enantioselective synthesis of nicotinic alkaloid 1 is presented. The route features the synthesis and use of a "stable" aliphatic triflate 21 in an alkylation step to generate Heck precursor 24 and an enantioselective cyclization to establish a compound with the key [3.2.1]-bicyclic core, 29.
Subject(s)
Molecular Probes , Nicotine/analogs & derivatives , Receptors, Nicotinic/chemistry , Crystallography, X-Ray , Models, Molecular , Nicotine/chemical synthesis , StereoisomerismABSTRACT
3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptors, Nicotinic/metabolism , Smoking Cessation/methods , Animals , Cyclization , Molecular Structure , Piperidines/classification , Rats , Structure-Activity RelationshipABSTRACT
The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
Subject(s)
Alkaloids/pharmacology , Carbon/chemistry , Dopamine/metabolism , Nicotinic Agonists/pharmacology , Nucleus Accumbens/drug effects , Receptors, Nicotinic/chemistry , Alkaloids/chemistry , Animals , Azocines/chemistry , Azocines/pharmacology , Nicotinic Agonists/chemistry , Quinolizines/chemistry , Quinolizines/pharmacology , Rats , Receptors, Nicotinic/metabolism , Smoking Cessation , Structure-Activity RelationshipABSTRACT
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
Subject(s)
Benzazepines/chemical synthesis , Nicotinic Agonists/chemical synthesis , Quinoxalines/chemical synthesis , Receptors, Nicotinic/drug effects , Smoking Cessation/methods , Animals , Benzazepines/chemistry , Benzazepines/pharmacology , Cell Line , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Humans , In Vitro Techniques , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Oocytes/drug effects , Oocytes/physiology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Radioligand Assay , Rats , Receptors, Nicotinic/physiology , Varenicline , Xenopus laevisABSTRACT
Oxidative ring closure of alkyl-substituted 2-hydroxyacetophenone trifluoromethanesulfonate esters (triflates) occurs upon exposure to base in anaerobic DMF at 20-90 degrees C. Alkyl substitution is required for ring closure. A migrated enol triflate product forms at lower temperature in high yield via migration of the trifluoromethanesulfonate in the unsubstituted and monoalkyl-substituted cases. The alkyl-substituted enol triflates also enter into the benzofuran-3-one ring-forming process under thermal cyclization conditions. Potential mechanistic pathways are evaluated.
