THE STRUCTURE-ACTIVITY RELATIONSHIP BETWEEN PHENYLENE-POLYMETHYLENE BIS-AMMONIUM DERIVATIVES AND THEIR NEUROMUSCULAR BLOCKING ACTION ON MOUSE PHRENIC NERVE-DIAPHRAGM MUSCLE

The structure-activity relationship of phenylene-polymethylene bis-amm onium (PMBA) derivatives, C6H4[X(CH2)(n)R](2), on isolated mouse phren ic nerve-diaphragm muscle was investigated to obtain more potent and s table compounds for use as pharmacological tools to clarify the mechan ism of succinylcholine (SuCh)-induced neuromuscular blockade. The neur omuscular blocking effect of all the PMBA derivatives was not reversed by neostigmine, a cholinesterase inhibitor. The potency of the neurom uscular blockade was in the order p- >o- >m- with respect to the side- chain substituents. A PMBA composed of X=CH2, n=5 and R=N(+)Et(3) was 5.9- and 23-fold more potent than SuCh and decamethonium, respectively . The derivatives of R=N(+)Et(3) were observed to be more potent than those of R=N(+)Me(3), N-Me-piperidino and pyridinio derivatives. Repla cement of X=CH2 with O, CHOH and CHOAc decreased the neuromuscular act ivity while replacement with S, SO and SO2 increased it. Introduction of NO2 into the phenylene ring increased the activity, while the intro duction of an alcohol, aldehyde and ketone group decreased it. Removal of a carbonyl or ether group from SuCh decreased its activity, wherea s the introduction of these into PMBA failed to increase it. We manage d to synthesized unhydrolyzable neuromuscular blocking agents which ar e more potent than SuCh.