Cardioselectivity of AQ-RA 741, a novel tricyclic antimuscarinic drug.

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.