Antagonists of serotonin 5-HT6 receptors. iv. synthesis and structure-activity interactions in amines containing the 3-(arylsulfonyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidine fragment

New 3-(arylsulfonyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidines with a substituent amino group in the 7 position were synthesized and their 5-HT 6 antagonist activity was studied. The transition from 7-amino and 7-dimethylamino derivatives to 7-aminoalkyl derivatives was found to lead to a significant decrease in activity; a similar pattern was seen on substitution of the methyl group in position 5 by a phenyl or thiophen-2-yl substituent. The most active (at the picomolar level) compounds were 5-methyl-2-(methylthio)-3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-7-amine and N,N,5,6-tetramethyl-2-(methylthio)-3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-7-amine (K i = 700 pM). The first member of the hydrogenated pyrazolo[1,5-a]pteridine class – 5,6,9-trimethyl-2-(methylthio)-3-(phenylsulfonyl)-6,7,8,9-tetrahydropyrazolo[1,5-a]pteridine (K i = 14.4 nM) was synthesized. These relationships between structure and 5-HT 6 antagonist activity support the adequacy of our pharmacophore model, such that it can be used for the further search for new highly effective 5-HT 6 antagonists.