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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Investigation of the interaction of a putative allosteric modulator, N-(2,3-diphenyl-1,2,4-thiadiazole-5-(2H)-ylidene) methanamine hydrobromide (SCH-202676), with M1 muscarinic acetylcholine receptors.

The interaction between a novel G protein-coupled receptor modulator, N-(2,3-diphenyl-1,2,4-thiadiazole-5-(2H)-ylidene) methanamine hydrobromide (SCH-202676), and the M(1) muscarinic acetylcholine receptor (mAChR) was investigated. In contrast to the prototypical mAChR allosteric modulator, heptane 1,7-bis-(dimethyl-3'-phthalimidopropyl)-ammonium bromide (C(7)/3-phth), SCH-202676 had no effect on the dissociation kinetics of [(3)H]N-methylscopolamine ([(3)H]NMS) at M(1) mAChRs stably expressed in Chinese hamster ovary (CHO) cell membranes. However, SCH-202676 completely inhibited the binding of [(3)H]NMS in membrane preparations, with a Hill slope significantly greater than unity, indicative of positive cooperativity in the binding of the inhibitor. Moreover, SCH-202676 caused dextral shifts of the [(3)H]NMS saturation binding curve that were greater than expected for a competitive interaction. The addition of C(7)/3-phth (100 microM) had no significant effect on the inhibitory potency of SCH-202676. In contrast to the findings in cell membranes, the interaction between SCH-202676 and [(3)H]NMS in intact M(1) CHO cells yielded saturation and inhibition isotherms that were compatible with the predictions for a competitive interaction. Intact cell assays of acetylcholine-mediated phosphoinositide hydrolysis in the absence or presence of SCH-202676 revealed a mixed competitive/noncompetitive mode of interaction that was dependent on the concentration of SCH-202676. These data reveal that the nature of the interaction between SCH-202676 and the M(1) mAChR is dependent on whether it is studied using intact versus broken cell preparations. It is proposed that SCH-202676 uses a dual mode of ligand-receptor interaction involving both extra- and intracellular attachment points on the M(1) mAChR that are distinct from the allosteric binding site recognized by prototypical mAChR modulators such as C(7)/3-phth.[1]


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