Pharmacological properties of cloned muscarinic receptors expressed in A9 L cells; comparison with in vitro models.
The effects of a series of muscarinic agonists and antagonists at cloned m1 and m3 muscarinic receptors expressed in mouse fibroblast A9 L cells have been compared with their effects in in vitro models of M1 (rat superior cervical ganglion) and M3 (guinea-pig ileum) muscarinic receptors. A good correlation existed between the potencies of muscarinic agonists at cloned m1 muscarinic receptors and the M1 sites in rat ganglion (r = 0.80) as well as at cloned m3 receptors and guinea-pig ileum M3 receptors (r = 0.87). However, cross correlations of potencies in rat ganglion and cloned m3 receptors as well as in guinea-pig ileum and in cloned m1 receptors also yielded relatively high correlation coefficients (0.71 and 0.91, respectively). Low correlation coefficients were found for the maximal responses of muscarinic agonists in rat ganglion and cloned m1 receptors (0.53) and in guinea-pig ileum and cloned m3 receptors (0.36). A high correlation between pA2 values of muscarinic antagonists at cloned m1 receptors and in rat ganglion (r = 0.97) and between cloned m3 receptors and guinea-pig ileum (r = 0.98) was found. Cross correlation of pA2 values in rat ganglion and cloned m3 receptors and in guinea-pig ileum and cloned m1 receptors yielded correlation coefficients of 0.82 and 0.72, respectively. The data indicate that the cloned muscarinic receptor sites seem similar to the corresponding endogenous sites. The good correlations in corresponding but also non-corresponding receptor models reflect the relatively low selectivity of the majority of the compounds investigated.
Boddeke
H W
HW
Preclinical Research, Sandoz Pharma Ltd., Basle, Switzerland.
Buttini
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D016257:Fura-2; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D010276:Parasympatholytics / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000235:genetics
D010276:Parasympatholytics; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D002118:Calcium; D016257:Fura-2