Synthesis, pharmacology, and molecular modeling studies of semirigid, nicotinic agonists.

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.

• Authors: J A Waters, C E Spivak, M Hermsmeier, J S Yadav, R F Liang, T M Gund
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 31 Issue 3 Pg. 545-54 (Mar 1988) ISSN: 0022-2623 [Print] United States
• PMID: 3258034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Ganglionic Stimulants
• isoarecolone methiodide
• Arecoline

Topics

• Animals
• Arecoline (analogs & derivatives, chemical synthesis, pharmacology)
• Computer Simulation
• Ganglionic Stimulants (chemical synthesis)
• In Vitro Techniques
• Models, Molecular
• Muscle Contraction (drug effects)
• Rana pipiens
• Software