Study on zwitter-ionization of drugs. II. Synthesis and pharmacological activity of some N-[3-(5H-dibenzo[a, d]cyclohepten-5-ylidene) propyl]-N-methylamino- and N-[3-(6H-dibenz[b, e]oxepin-11-ylidene) propyl]-N-methylamino-alkanoic acid derivatives and related compounds.
A series of N-[3-(5H-dibenzo[a, d]cyclohepten-5-ylidene)propyl]-N-methylamino- (6a) and N-[3-(6H-dibenz-[b, e]oxepin-11-ylidene)propyl]-N-methylamino-alkanoic acid derivatives (6b) and related compounds (6c-f) were synthesized and examined for pharmacological activities in vitro, i.e., inhibitory effect on monoamine [noradrenaline (NA) and 5-hydroxytryptamine (5-HT)] uptake, inhibitory effect on 5-HT-, histamine-, acetylcholine- and NA-induced contraction, and binding affinity for alpha 2-adrenoceptor and dopamine D2-receptor. In vitro tests indicated that zwitter-ionization was capable of maintaining H1-antihistaminic activity while greatly reducing other pharmacological activities. Further, 6a-f showed much stronger inhibitory effects on compound 48/80-induced lethality in rats than did the corresponding N,N-dimethylamines (2a-f). 3-[N-[3-(6H-Dibenz[b, e]oxepin-11-ylidene)propyl]-N-methylamino]- 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 48 h homologous passive cutaneous anaphylaxis (PCA) in rats (ED50 = 0.019 mg/kg, p.o.) and on histamine-induced bronchoconstriction in anesthetized guinea-pigs (ED50 = 0.0067 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
D000639:Amitriptyline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors*; D004316:Doxepin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009125:Muscle Relaxants, Central / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017982:Receptors, Biogenic Amine / Q000187:drug effects; D011969:Receptors, Histamine H1 / Q000187:drug effects; D013329:Structure-Activity Relationship
D015306:Biogenic Monoamines; D009125:Muscle Relaxants, Central; D017982:Receptors, Biogenic Amine; D011969:Receptors, Histamine H1; D004316:Doxepin; D000639:Amitriptyline; C004704:cyclobenzaprine