[Studies on zwitter-ionization of drugs. III. Synthesis and pharmacological activities of N-alkylcarboxylic acid derivatives of 1,2,3,4,10,14b-Hexahydrodibenzo[c,f]-pyrazino[1,2-a]azepine and 2,3,4,9-tetrahydro-1H-dibenzo[3,4: 6,7]cyclohepta[1,2-c]pyridine].
The N-alkylcarboxylic acids of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-alpha]az epi ne (6a) and 2,3,4,9-tetrahydro-1H-dibenzo[3,4: 6,7]cyclohepta[1,2- c]pyridine (6b) were synthesized and examined for pharmacological activities in vitro: an inhibitory effect on the monoamine [noradrenaline (NA) and 5-hydroxytryptamine (5-HT)] uptake into the rat crude synaptosome, an inhibitory effect on the 5-HT- and NA-induced contraction in the isolated rabbit aorta and on the histamine- and acetylcholine-induced contraction in the isolated guinea-pig ileum, and binding affinity for alpha 2-adrenoceptor and D2-receptor. The in vitro tests indicated that zwitter-ionization was capable of maintaining antihistaminic activity while greatly reducing other pharmacological activities such as effects on central nervous system. 3-[2,3,4,9-Tetrahydro-1H-dibenzo[3,4: 6,7]cyclohepta[1,2- c]pyridin-2-yl]propionic acid (6b-2), selected as a candidate antiallergic agent having equally potent activities 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 anesthetized guinea-pigs (ED50 = 0.0088 mg/kg, p.o.).
Muramatsu
H
H
First Division of the Research Laboratory for Development of Medicine, Hokuriku University, Ishikawa, Japan.
Sawanishi
H
H
Iwasaki
N
N
Kakiuchi
M
M
Ohashi
T
T
Kato
H
H
Ito
Y
Y
D000818:Animals; D000893:Anti-Inflammatory Agents; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001552:Benzazepines; D011725:Pyridines; D012701:Serotonin; D009638:Norepinephrine