SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF SOME AMINO-ACID-CONTAINING CYPROHEPTADINE DERIVATIVES AS DUAL ANTAGONISTS OF HISTAMINE H-1-RECEPTOR AND LEUKOTRIENE D-4-RECEPTOR

A novel series of cyproheptadine derivatives, in which an amino acid o r a dipeptide moiety was introduced at the piperidine nitrogen, have b een synthesized. The amino acid and dipeptide moieties were taken as p art of leukotriene D-4 (LTD(4)) pharmacophore. This modification reduc ed the H-1-antihistamine activity (100-1000-fold) but elevated the ant i-LTD(4) activity (10-100-fold) of the compounds, as compared with cyp roheptadine. As a result, some of the new compounds, especially the al pha-amino-propionic acid derivatives 4, are well-balanced dual antagon ists of histamine and LTD(4) with both activities at micromolar range. Radioligand binding studies have confirmed that the new compounds, bu t not cyproheptadine for LTD(4), exert their action through competetiv e occupation of the receptors. One compound, yloxycarbonyl-amino-3-[4- (10,11-dihydro-5H-dibenzo [a,d]cyclo-hepten-5-yloxy)piperidin-1-yl]pro pionic acid (4c), was tested in an in vitro guinea-pig asthma model. I t exhibits much more potent inhibition (IC50 = 1.5 mu M) against antig en-induced contraction than either terfenadine or FPL55712, the refere nce drugs. As indicated by an ex vivo binding assay, the drug 4c does not readily pass the blood-brain barrier, and therefore is unlikely to cause sedating side-effects at a therapeutic dose.