Pharmacological profiles for rat cortical M1 and M2 muscarinic receptors using selective antagonists: comparison with N1E-115 muscarinic receptors.
We previously showed that M1 and M2 muscarinic receptors in dissociated cells of the adult rat cortex couple to phosphoinositide (Pl) and cyclic AMP (cAMP) metabolism, respectively. To further classify these receptors according to probable subtype, we have employed a group of selective muscarinic antagonists to obtain pharmacological profiles of the cortical M1 and M2 receptors, and to compare them with the muscarinic receptors in N1E-115 cells, which contain M1 receptors mediating cyclic GMP elevation and M4 receptors inhibiting cAMP levels. The M2-mediated inhibition of cAMP levels in cortex was blocked by 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP) with higher potency (0.29 nM) than for reported potency in cardiac tissue (approximately 10 nM), indicating that this cortical response is probably not mediated by the m2 gene product. Similarly, the potency of hexahydrosiladiphenidol (HSD) at the cortical M2 receptor (159 nM) was somewhat greater than the reported potency in cardiac tissue (295 nM). The cardioselective drugs AF-DX 116 and methoctramine blocked the cortical M2 response less potently (135 nM and 229 nM, respectively) than would be expected for involvement of the m2 gene product. Thus, the potencies of AF-DX 116, methoctramine, 4-DAMP and HSD suggest that the cortical M2 response, like the striatal M2 receptor, is mediated by a noncardiac M2 receptor, perhaps by the m4 gene product. This postulate was supported by the significant correlations between cortical and striatal M2 receptors as compared to the M4 receptor in N1E-115 cells (r = 0.92 and 0.99, respectively, P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)
McKinney
M
M
Neuropharmacology Laboratory, Mayo Clinic Jacksonville, Florida.
Anderson
D J
DJ
Vella-Rountree
L
L
Connolly
T
T
Miller
J H
JH
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D003959:Diamines / Q000494:pharmacology; D066298:In Vitro Techniques; D018727:Muscarinic Antagonists; D010276:Parasympatholytics / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000145:classification; D014407:Tumor Cells, Cultured
D003959:Diamines; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010627:Phenethylamines; D010716:Phosphatidylinositols; D010880:Piperidines; D011976:Receptors, Muscarinic; C058297:4-fluorohexahydrosiladifenidol; D010890:Pirenzepine; C028187:secoverine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D000242:Cyclic AMP; C046773:hexahydrosiladifenidol; C054938:methoctramine; C048593:otenzepad