TY - JOUR T1 - Antagonist binding profiles of five cloned human muscarinic receptor subtypes. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 727 LP - 733 VL - 256 IS - 2 AU - F Dörje AU - J Wess AU - G Lambrecht AU - R Tacke AU - E Mutschler AU - M R Brann Y1 - 1991/02/01 UR - http://jpet.aspetjournals.org/content/256/2/727.abstract N2 - A variety of muscarinic antagonists are currently used as tools to pharmacologically subclassify muscarinic receptors into M1, M2 and M3 subtypes. In the present study, we have determined the affinity profiles of several of these antagonists at five cloned human muscarinic receptors (m1-m5) stably expressed in Chinese hamster ovary cells (CHO-K1). At all five receptors, the (R)-enantiomers of trihexyphenidyl and hexbutinol displayed considerably higher affinities (up to 525-fold) than their corresponding (S)-isomers. The stereoselectivity ratios [inhibition constant(S)/inhibition constant(R)] for both pairs of enantiomers were lowest at m2 receptors, suggesting that less stringent configurational demands are made by this receptor subtype. The "M1-selective" antagonist (R)-trihexyphenidyl displayed high affinities for m1 and m4 receptors. The "M2-selective" antagonists himbacine, (+-)-5,11-dihydro-11- ([(2-[(dipropylamino)methyl]-1- piperidinyl)ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(1,4)benzodiazepine-6- one (AF-DX 384), 11-[4-[4-(diethylamino)butyl]-1-piperidinyl)acetyl)-5,11- dihydro-6H-pyrido(2,3-b) (1,4)benzodiazepine-6-one (AQ-RA 741) and (+)-(11-[2-[(diethylamino) methyl]-1-piperidinyl)acetyl)-5,11-di-hydro-6H-pyrido(2,3-b)(1,4) benzodiazepine-6-one [AF-DX 250; the (+)-enantiomer of AF-DX 116] exhibited high affinities for m2 and m4, intermediate affinities for m1 and m3 and low affinities for m5 receptors. This selectivity profile was most prominent for AQ-RA 741, which displayed 195- and 129-fold higher affinities for m2 and m4 receptors than for m5 receptors.(ABSTRACT TRUNCATED AT 250 WORDS) ER -