STUDIES ON ZWITTER-IONIZATION OF DRUGS .3 . SYNTHESIS AND PHARMACOLOGICAL ACTIVITIES OF N-ALKYLCARBOXYLIC ACID-DERIVATIVES OF 0,14B-HEXAHYDRODIBENZO[C,F]-PYRAZINO[1,2-A]AZEPINE AND HYDRO-1H-DIBENZO[3,4-6,7]CYCLOHEPTA[1,2-C]PYRIDINE

The N-alkylcarboxylic acids of 0,14b-hexahydrodibenzo[c,f]py-razino[1, 2-a]azepine (6a) and 2,3,4,9-tetrahydro-1H-dibenzo[3,4 : 6,7]cyclohe-p ta[1,2-c]pyridine (6b) were synthesized and examined for pharmacologic al activities in vitro: an inhibitory effect on the monoamine [noradre naline (NA) and 5-hydroxytryptamine (5-HT)] uptake into the rat crude synaptosome, an inhibitory effect on the 5-HT- and NA-induced contract ion in the isolated rabbit aorta and on the histamine- and acetylcholi ne-induced contraction in the isolated guinea-pig ileum, and binding a ffinity for alpha2-adrenoceptor and D2-receptor. The in vitro tests in dicated that zwitter-ionization was capable of maintaining antihistami nic activity while greatly reducing other pharmacological activities s uch as effects on central nervous system. 3-[2,3,4,9-Tetrahydro-1H-dib enzo[3,4 : 6,7]cyclohepta[1,2-c]pyridin-2-yl]propionic acid (6b-2), se lected as a candidate antiallergic agent having equally potent activit ies in rats and guinea-pigs, exhibited strong inhibitory effects on 48 h homologous passive cutaneous anaphylaxis (PCA) in rats (ED50=0.012 mg/kg, p.o.) and on histamine-induced bronchoconstriction in anestheti zed guinea-pigs (ED50= 0.0088 mg/kg, p.o.).