title: Cardioselectivity of AQ-RA 741, a novel tricyclic antimuscarinic drug.
abstract: The interaction of the AF-DX 116 analogue, AQ-RA 741 (11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl]-5,11- dihydro-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one), with muscarinic receptors, in vitro and in vivo, was examined. In radioligand binding studies, AQ-RA 741 showed high affinity for cardiac M2 sites (pKi = 8.30), intermediate affinity for cortical M1 sites (pKi = 7.70) and low affinity for glandular M3 sites (pKi = 6.82). Functional studies showed AQ-RA 741 to be a competitive antagonist and to have a 60 to 87-fold higher affinity for cardiac muscarinic receptors than for muscarinic receptors in intestinal, tracheal or bladder smooth muscle. In vivo experiments confirmed the M2 selectivity of AQ-RA 741. In rats, cats and guinea-pigs AQ-RA 741 preferentially inhibited the vagally or agonist-induced bradycardia (-log ID50 = 7.24-7.53 i.v.). The ratio of potencies observed between effects mediated by cardiac and other muscarinic receptor ranged between 9- and more than 100-fold. The results show that AQ-RA 741 is a potent and selective M2 antagonist with remarkable in vivo selectivity.
authors.affiliation: Department of Pharmacology, Dr. Karl Thomae GmbH, Biberach, F.R.G.
authors.forename: H
authors.initials: H
authors.lastname: Doods
authors.forename: M
authors.initials: M
authors.lastname: Entzeroth
authors.forename: N
authors.initials: N
authors.lastname: Mayer
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002415:Cats; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects
chemical_list: D001570:Benzodiazepinones; D010276:Parasympatholytics; D010880:Piperidines; D011976:Receptors, Muscarinic; C069054:AQ-RA 741; D010890:Pirenzepine; C048593:otenzepad