Structure-activity relationships and pharmacological profile of selective tricyclic antimuscarinics

Abstract

The discovery of the M1-selective receptor antagonist pirenzepine was the impetus for a research project directed towards the development of selective muscarinic antagonists. In the pursuit of this objective, compounds with different selectivity profiles have been found. AF-DX 116 was the first cardioselective antagonist synthesized. Subsequently novel M2 receptor antagonists have been discovered with higher potency and selectivity. Moreover, a pirenzepine-type compound UH-AH 37 has been identified that, in contrast to pirenzepine, shows a higher affinity for ileal than for atrial muscarinic receptors. Among tricyclic muscarinic receptor antagonists three different selectivity profiles have been identified, namely: M1 greater than M3 greater than M2, Msm for pirenzepine; M2 greater than M1 greater than M3, Msm for AF-DX 116, AF-DX 384, AQ-RA 741; and Msm congruent to M1 greater than M2, M3 for UH-AH 37 and its (+) enantiomer.