Antihistaminic/antiallergic activity of 2-dialkylaminoalkylthio(oxy)-1-substituted benzimidazoles: evaluation "in vitro" and "in vivo".
A new series of 2-dialkylamino-alkylthio(oxy)-1-substituted benzimidazoles synthesized in our laboratories was found to have promising antihistaminic activity. The results of pharmacological screening ("in vitro": radioreceptor binding and isolated organs; "in vivo": protection against mortality induced by histamine or by compound 48/80, passive cutaneous anaphylaxis, and prolongation of barbiturate-induced sleeping-time) gave clear-cut structure-activity relationships. This series of products has a general selectivity towards H1 receptors, weak antiallergic properties and negligible central effects. DF 10967 (1-ethoxyethyl-2-dimethyl-aminoethylthiobenzimidazole) was the most interesting compound, being very potent both "in vitro" (Ki = 3.2 +/- 0.8 nM) and "in vivo" (ID50 11 micrograms/kg, i.p. and 8 micrograms/kg, i.p. against histamine- and 48/80-induced mortality), with no central effects. The last finding is probably due to poor penetration into the brain (as confirmed by "in vivo" binding test with [3H]-mepyramine) and to lack of interaction with other central receptors.
Research and Development Department, DOMPE Farmaceutici S.p.A., Milan, Italy.
S
S
Dini
G F
GF
Caselli
C
C
Basilico
A
A
Lavezzo
R
R
Giani
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001562:Benzimidazoles; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002974:Clemastine / Q000494:pharmacology; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006967:Hypersensitivity / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D011738:Pyrilamine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013440:Sulfides / Q000494:pharmacology*; D016593:Terfenadine; D003189:p-Methoxy-N-methylphenethylamine / Q000633:toxicity
D001559:Benzhydryl Compounds; D001562:Benzimidazoles; D006633:Histamine Antagonists; D007093:Imidazoles; D013440:Sulfides; C064932:1-ethoxyethyl-2-dimethylaminoethylthiobenzimidazole; D003189:p-Methoxy-N-methylphenethylamine; D016593:Terfenadine; C029899:imidazole; D002974:Clemastine; D011738:Pyrilamine