CYPROHEPTADINE ANALOGS - SYNTHESIS, ANTISEROTONINERGIC ACTIVITY, AND STRUCTURE-ACTIVITY-RELATIONSHIPS

A series of cyproheptadine related compounds was synthesized and teste d pharmacologically. In comparison with cyproheptadine, these compound s do not have a central ring and some contain groups other than N-meth yl. Synthesis was carried out with low-valent titanium to generate the exocyclic double bond. The serotoninergic activity of the compounds w as determined by standard determination of pA2 (-log of the motor conc entration of antagonist required to maintain a constant response when concentration of agonist is doubled) for the inhibition of serotonin-i nduced contractions in rat stomach fundus. Two of the nitrogen-contain ing compounds were active, but their activities were lower than that o f cyproheptadine. Structure-activity relationships were studied by Mul liken net charges, molecular electrostatic potentials, and conformatio nal analysis; activities are better correlated with electrostatic pote ntials than with net charges. The decrease in potency of the open cypr oheptadine analogues may be due to ''dilution'' of the active conforme r as the result of their conformational flexibility.