Synthesis, Pharmacology, and Molecular Modeling Studies of Semirigid, Nicotinic Agonists

James A. Waters, Charles E. Spivak, Mark Hermsmeier, Janardan S. Yadav, Rong F. Liang, Tamara Gund

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Eight nicotinic agonists were synthesized, and their potencies were estimated by contracture of the frog rectus abdominis muscle. The most potent, 1-methyl-4-acetyl-1,2,3,6-tetrahydropyridine methiodide (3b), 50 times as potent as carbamylcholine, served as a template for the rest. Although all of the agonists could easily conform to the putative nicotinic pharmacophore, their potencies spanned a nearly 10 000-fold range. This pharmacophore, therefore, may be necessary but deficient. Computer-assisted molecular modeling studies helped to delineate additional factors that may contribute to potency. The factors are (1) the ground-state conformation, (2) superimposability of the hydrogen bond acceptor and the cationic head onto the template, (3) electrostatic potential at the cationic head and at the hydrogen bond acceptor site, and (4) the presence of a methyl group bonded to the carbon atom that bears the hydrogen bond acceptor. A new program, archem, was used to calculate and to visualize electrostatic potentials at the van der Waals surfaces of the agonists.

Original languageEnglish (US)
Pages (from-to)545-554
Number of pages10
JournalJournal of Medicinal Chemistry
Volume31
Issue number3
DOIs
StatePublished - Mar 1 1988

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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