Differential stimulation of inositol phospholipid turnover in brain by analogs of oxotremorine.
Structural analogs of oxotremorine have been employed to examine the relationship between the binding of agonists to muscarinic receptors in guinea pig cerebral cortex and the enhancement of inositol lipid turnover. Large differences were observed in the ability of the analogs to stimulate inositol phospholipid turnover, as measured both by the increase in labeling of phosphatidate and phosphatidylinositol from 32Pi in a nerve-ending fraction, and by the stimulated release of labeled inositol phosphates from slices of cerebral cortex, a direct measure of inositol lipid breakdown. The quaternary N+ analogs, oxotremorine-M and its N-methylacetamide derivative, were five to thirteen times as effective as oxotremorine. In contrast, methyl substitution of the pyrrolidone ring of oxotremorine resulted in a complete loss of agonist activity. Receptor occupancy data obtained from the displacement of labeled quinuclidinyl benzilate bound to receptors in a nerve-ending fraction indicated that the more efficacious agonists interacted with at least two affinity forms of the muscarinic receptor, whereas the less effective agonists bound to a single affinity form. Dose-response curves obtained in the presence of oxotremorine-M for inositol lipid turnover in both the nerve-ending fraction and slice preparation correlated with the occupancy of a single low-affinity form of the muscarinic receptor. The results suggest that the differential abilities of analogs of oxotremorine to enhance inositol lipid turnover in brain are closely related to the extent of agonist-induced conformational change in the muscarinic receptor.
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D007295:Inositol Phosphates / Q000378:metabolism; D010095:Oxotremorine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship
D007295:Inositol Phosphates; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; C042744:N-methylacetamide-oxotremorine M; D010095:Oxotremorine; C042743:oxotremorine M; D011813:Quinuclidinyl Benzilate