Biochemical and behavioral responses of pilocarpine at muscarinic receptor subtypes in the CNS. Comparison with receptor binding and low-energy conformations.
Pilocarpine was tested biochemically in vitro for its ability to stimulate phosphoinositide (PI) turnover in the hippocampus (M1/M3 responses) where it displayed 35% of the maximal carbachol response with an EC50 value of 18 microM, and low-Km GTPase in the cortex (M2 response), where it had 50% of the maximal carbachol response with an EC50 value of 4.5 microM. Behaviorally, pilocarpine was able to restore deficits in a representational memory task (sensitive to M1 antagonists) produced by intrahippocampal injections of AF64A. Twenty-three low-energy conformations of protonated pilocarpine were generated using the program MacroModel. The data indicate that pilocarpine is a partial agonist at both M1 and M2 muscarinic receptors in the CNS. Behaviorally, with respect to the memory task, M1 effects of pilocarpine apparently predominate. It also is conceivable that different conformations of pilocarpine are active as agonists at different muscarinic receptor subtypes.
Hoss
W
W
Department of Medicinal and Biological Chemistry, University of Toledo, College of Pharmacy, OH 43606.
Woodruff
J M
JM
Ellerbrock
B R
BR
Periyasamy
S
S
Ghodsi-Hovsepian
S
S
Stibbe
J
J
Bohnett
M
M
Messer
W S
WS
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010716:Phosphatidylinositols / Q000378:metabolism; D010862:Pilocarpine / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects*
D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D020558:GTP Phosphohydrolases