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
| Autor: | Hiroyuki Sawanishi, Hiromi Muramatsu, H. Kato, Tetsuo Ohashi, Nobuhiko Iwasaki, Masato Kakiuchi, Y. Ito |
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| Rok vydání: | 1993 |
| Předmět: |
Male
Stereochemistry Amitriptyline Guinea Pigs Mice Inbred Strains In Vitro Techniques chemistry.chemical_compound Mice Structure-Activity Relationship Dopamine Receptors Biogenic Amine Drug Discovery medicine Animals Biogenic Monoamines Receptors Histamine H1 Rats Wistar ED50 Molecular Structure Muscle Relaxants Central Biological activity General Chemistry General Medicine Rats Monoamine neurotransmitter chemistry Antiallergic agent Zwitterion Doxepin Rabbits Acetylcholine Histamine medicine.drug |
| Zdroj: | Chemicalpharmaceutical bulletin. 41(11) |
| ISSN: | 0009-2363 |
| Popis: | 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.). |
| Databáze: | OpenAIRE |
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