Affinity and selectivity at M2 and M3 muscarinic receptor subtypes of cyclic and open oxygenated analogues of 4-DAMP

Two series of cyclic (13-24) and open (25-33) phenyl substituted analogues of 1,1-dimethyl-4-diphenylacetyloxy-piperidinium iodide (4-DAMP, 1) have been synthesized and tested to evaluate their affinity and selectivity for M2 and M3 muscarinic receptor subtypes of isolated guinea pig left atrium and ileum, respectively. A corresponding series of phenyl substituted derivatives (4-11) of 4-DAMP (1) have been synthesized and tested for comparison. The parent compounds spiro-DAMP (2) and hydroxy-DAMP (3) were very active but not selective antagonists at either M2 and M3 receptor subtypes. The high pA2 values of spiro-DAMP (2) suggest that the position in which groups contributing to activity are held by the rather rigid structure is suitable for a productive binding. Moreover, the ether bridge of spiro-DAMP (2) and the hydroxy group of hydroxy-DAMP (3) provide additional binding interactions, particularly in the case of 3. Phenyl substituents on all three structures did not improve significantly the selectivity of 4-DAMP (1) for either M2 and M3 muscarinic receptor subtypes, their effects being limited to affinity. The volume of substituents has a negative influence on the affinity, weakly counter-balanced by positive lipophilic interactions. Substitution of a cyclohexyl ring for one of the phenyl rings (12, 24, 33) improves affinity.