ABSTRACT
Studies are described dealing with the molecular features of nicotine, the receptor binding and psychotropic properties of nicotine agonists and antagonists, and the neuroanatomical locus of action of nicotine associated with its psychotropic action. Bridged analogues of nicotine have been developed to define the optimal conformation of the molecule for maximal receptor affinity and psychotropic action in rats. With another series of analogues, it was demonstrated that contraction of the pyrrolidine ring to a 4-member azetidine enhances potency while expansion diminishes it. A major site for nicotine's central action is the vestibular cerebellum as demonstrated by kainic acid lesioning studies and direct administration of nicotine into this region. Included among the antagonists to nicotine was alpha-lobeline, which appeared to be a mixed agonist-antagonist.
Subject(s)
Brain/drug effects , Nicotine/pharmacology , Receptors, Nicotinic/drug effects , Smoking/physiopathology , Animals , Arousal/drug effects , Arousal/physiology , Brain/physiopathology , Brain Mapping , Cerebellum/drug effects , Cerebellum/physiopathology , Dose-Response Relationship, Drug , Humans , Nicotine/analogs & derivatives , Nicotine/antagonists & inhibitors , Rats , Receptors, Nicotinic/physiology , Structure-Activity Relationship , Vestibular Nuclei/drug effects , Vestibular Nuclei/physiopathologyABSTRACT
The recently discovered nicotinic agonist pyrido[3,4-b]norhomotropane [corrected] (PHT) as well as its N-methyl and 2'-methyl derivatives (syntheses reported herein) were compared with nicotine, nornicotine, and anatoxin a in a series of in vitro and in vivo assays. The results reveal that PHT possesses activity comparable to that of the highly potent agonist, anatoxin a. The inactivity observed relative to PHT of N-methyl- and 2'-methyl-PHT has helped to further define the structure-activity requirements of conformationally restricted nicotinoids.
