Search

It is proposed, based upon comparisons with apomorphine, that the rigid pyrroleethylamine moiety of the ergolines is the portion of the molecule responsible for dopamine agonist activity. In support of this hypothesis, bicyclic and tricyclic ergoline partial structures 6, 11, 25, and 35 have been synthesized. In addition, some pyrazole isosters (37, 38, 40, and 45) of these rigid pyrroleethylamines have been made. All of the classes show dopaminergic activity in prolactin inhibition and in lesioned rat turning assays. The most potent drugs, the linear tricyclic pyrazoles 38 (R = Pr) and 40 (R = Pr), are comparable in potency with the highly active ergoline pergolide (41).

The synthesis and antirhinovirus activity of syn and anti isomers of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine (4 and 5) are reported. The structural assignments of 4 and 5 are based upon 13C NMR spectra of both isomers and also X-ray analysis of 5. The anti-isomer 5 was more potent than the syn-isomer 4 when compared as an inhibitor of rhinovirus multiplication in vitro. Both isomers inhibited multiplication of 15 different serotypes of rhinovirus.

The levels of antidopaminergic and anticholinergic activities of neuroleptics, 4-piperazinyl-10H-thienobenzodiazepines, are modulated by imposing steric impedence to the piperazine ring. The optimum situation in favor of the anticholinergic action is reached in compound 5, 2,3-dimethyl-7-fluoro-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, where a maximum activity (equivalent to hyoscine), as measured by the [3H]QNB receptor binding assay, is obtained. The structure-activity relationships found highlight the importance of certain spatial dispositions of the distal piperazine nitrogen (electron lone pair) with respect to the tricyclic system. The evidence for molecular topography of these compounds is presented from X-ray, NMR, and other physical data. The conformational aspects for correspondence to the relevant receptors are discussed.