RELATIONSHIP BETWEEN STRUCTURE AND ACTIVITY IN A SERIES OF BIS-ISOQUINOLINIUM COMPOUNDS

¹ Department of Pharmacology, University of Illinois College of Medicine, Chicago 12, Illinois

1. A number of polymethylene bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro isoquinoline-1) dimethiodide derivatives from tetra- to dodecamethylene were investigated for their actions on the neuromuscular junction, cholinesterase, and sympathetic ganglia.

2. Curariform activity was related to the length of the polymethylene chain. The most potent derivatives in mammals were the hepta- to decamethylene compounds; in frogs the dodecamethylene derivatives were most potent. The addition of methoxy groups in the 8, 8' positions, or the substitution of ethyl-methyl for dimethyl on nitrogen did not alter potency appreciably. The most potent derivatives were about twice as active as tubocurarine in the rabbit.

3. The polymethylene bis-isoquinolinium compounds blocked the action of acetylcholine on the frog rectus muscle without producing a contracture; they produced flaccid paralysis in birds.

4. The degree of antagonism of the effects of the bis-isoquinolinium compounds by neostigmine was related to the length of the polymethylene chain between isoquinolinium nuclei. The degree of the reversibility of the compound by neostigmine was inversely related to the curariform activity of the compound.

5. The degree of inhibition of erythrocyte cholinesterase was related to the length of the polymethylene bridge between isoquinolinium nuclei, and this property paralleled curariform activity.

6. Transmission in the superior cervical ganglion of the cat was not diminished by any of the compounds in doses that produced at least 75 per cent paralysis of the anterior tibial muscle.