A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogs of the alkaloid pumiliotoxin B (8-hydroxy-8-methyl-6-alkylidene-1-azabicyclo[4.3.0]nonanes)

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Abstract
Pumiliotoxin B (PTX-B, 6-(6'',7''-dihydroxy-2'',5''-dimethyl-(E)-4''-octenylidene)-8-hydroxy-8-methyl-1-azabicyclo[4.3.0]nonane) increases the force of contractures spontaneously beating guinea pig atrial strips by 3- to 5-fold with half-maximal effect at .apprx. 3 .mu.M and increases rates of atrial contractions by 2- to 3-fold with half-maximal effects at .apprx. 6 .mu.M. The presence of an atrial 7-hydroxy substituent (PTX 339A) decreases the efficacy but not the potency of PTX-B as a positive inotropic agent, while having only slight effects on activity as a positive chronotropic agent. The presence of an equatorial 7-hydroxy substituent (PTX 339B) greatly decreases efficacy and potency of PTX-B as a positive chronotropic and inotropic agent. Pumiliotoxin A which lacks the side-chain 7''-hydroxy group of PTX-B causes only a 2-fold increase in force of contracture at 54 .mu.M, while having minimal effects on rate. The presence of an axial 7-hydroxy substituent (PTX 323B'' and 323B", epimeric at the 6''hydroxy) markedly enhances positive inotropic and chronotropic effects of PTX-A. Another congener, PTX 251D with a 6-(2''-methylhexylidene) side chain, and a synthetic analog with a 6-(6''-heptenylidene) side chain are cardiac depressants. Both lack hydroxyl groups in the side chain. The presence of an .omega.-1 hydroxy group in the side chain of PTX 251D yields an alkaloid (267C) with weak positive inotropic effects and minimal chronotropic effects. The presence of an axial 7-hydroxy group in the indolizidine ring of PTX 251D results in a compound (PTX 267A) with very weak positive inotropic effects while retaining the negative chronotropic effects of PTX 251D. A synthetic analog with a 6-(7''-hydroxyheptylidene) side chain is a cardiac depressant even though it contains a side-chain hydroxyl corresponding in position to the 7''-hydroxyl of the side chain of PTX-B. The positive chronotropic and inotropic effects of pumiliotoxin B are reversed only by relatively high concentrations of the Ca channel blockers nifedipine and verapamil, suggesting that pumiliotoxin B may owe its cardiotonic activities to effects on internal mobilization of Ca.

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