STUDY ON ZWITTER-IONIZATION OF DRUGS .2. SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF SOME CLOHEPTEN-5-YLIDENE)PROPYL]-N-METHYLAMINO-ALKANOIC AND E]OXEPIN-11-YLIDENE)PROPYL]-N-METHYLAMINO-ALKANOIC ACID-DERIVATIVES AND RELATED-COMPOUNDS

A series of o[a,d]cyclohepten-5-ylidene)propyl]-N-methylamino- (6a) an d e]oxepin-11-ylidene)propyl]-N-methylamino-alkanoic acid derivatives (6b) and related compounds (6c-f) were synthesized and examined for ph armacological activities in vitro, i.e., inhibitory effect on monoamin e [noradrenaline (NA) and 5-hydroxytryptamine (5-HT)] uptake, inhibito ry effect on 5-HT-, histamine-, acetylcholine- and NA-induced contract ion, and binding affinity for alpha2-adrenoceptor and dopamine D2-rece ptor. In vitro tests indicated that zwitter-ionization was capable of maintaining H-1-antihistaminic activity while greatly reducing other p harmacological activities. Further, 6a-f showed much stronger inhibito ry effects on compound 48/80-induced lethality in rats than did the co rresponding N,N-dimethylamines (2a-f). oxepin-11-ylidene)propyl]-N-met hylamino]-propionic acid (6b-2), selected as a candidate antiallergic agent of a new type, equally potent in rats and guinea-pigs, exhibited strong inhibitory effects on 48h homologous passive cutaneous anaphyl axis (PCA) in rats (ED50=0.019 mg/kg, p.o.) and on histamine-induced b ronchoconstriction in anesthetized guinea-pigs (ED50 = 0.0067 mg/kg, p .o.).