ABSTRACT
A series of benzamides was synthesized as selective agonists for the 5-HT1A receptor. It was found that (S)-N-[[1-(2-phenylethyl)pyrrolidin-2-yl]methyl]cyclohexanecarb oxamide(7-(S)) has potent and selective agonistic activity for the 5-HT1A receptor (5-HT1A; Ki 0.49 nmol/L, D2; IC50 = >1000 nmol/L, 5-HT2; Ki = 240 nmol/L).
Subject(s)
Amides/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemical synthesis , Amides/pharmacology , Animals , Binding, Competitive/drug effects , In Vitro Techniques , Neurons/drug effects , Neurons/metabolism , Pyrrolidines/pharmacology , Raphe Nuclei/cytology , Raphe Nuclei/drug effects , Raphe Nuclei/metabolism , Rats , Receptor, Serotonin, 5-HT2A , Receptors, Dopamine D2/drug effects , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1 , Serotonin Receptor Agonists/pharmacologyABSTRACT
A number of new carboxamide derivatives were synthesized. The affinity of these compounds for the serotoninergic 5-HT(4) receptor was evaluated by use of radioligand-binding techniques. The agonistic activity was evaluated as the contractile effect of the ascending colon isolated from guinea-pigs. Among these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[2-[(methylsulfonyl)amino]ethly]-4-piperidinylmethyl]benzamide (24) showed a high affinity for the 5-HT(4) receptor (Ki = 9.6 nM). Compound 24 displayed a higher affinity for 5-HT(4) receptors than the other receptors, including, 5-HT(3) and dopamine D(2) receptors. In addition, compound 24 was confirmed to be a potent 5-HT(4) receptor agonist (ED(50) = 7.0 nM). An interaction model between compound 24 and 5-HT(4) receptor was proposed.
ABSTRACT
Griseofulvin derivatives, dl-6'-demethyl-6'-ethylgriseofulvin (dl-5) and dl-6'demethyl-6'phenylgriseofulvin (dl-6) were prepared by application of a synthetic method developed by us. Antifungal activity of these derivatives decreased in the order of dl-griseofulvin (dl-1) >> dl-6(inactive). The reaction of these derivatives with ethanethiol gave two types of compounds, 2'-(ethylthio)griseofulvin (15) and 4'-(ethylthio)isogriseofulvin (16). The relationship between the ratios of isolated yield of 15 and 16 and antifungal the activity of griseofulvin derivatives is discussed.
Subject(s)
Antifungal Agents/chemical synthesis , Griseofulvin/analogs & derivatives , Antifungal Agents/pharmacology , Griseofulvin/chemical synthesis , Griseofulvin/chemistry , Griseofulvin/pharmacology , Microbial Sensitivity Tests , Trichophyton/drug effectsABSTRACT
dl-Griseofulvin (1a) was prepared by two synthetic pathways. New 6'-congeners (3 and 4) of griseofulvin were also prepared. Their antifungal activities were evaluated and compounds 3 and 4 were found to be less active than 1a. Molecular calculations on 1a, dl-epigriseofulvin (1b), 3 and 4 were undertaken.
