Synthesis and structure-activity relationships of a new model of arylpiperazines. Part 7: Study of the influence of lipophilic factors at the terminal amide fragment on 5-HT1A affinity/selectivity

The influence of lipophilic factors at the amide fragment of a new series of (±)-7a-alkyl-2-[4-(4-arylpiperazin-1-yl)butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazoles 2 and of (±)-7a-alkyl-2-[(4-arylpiperazin-1-yl)methyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazoles 3 has been studied. Variations of logP have been carried out by introducing different hydrocarbonated substituents (R1) at the position 7a of the bicyclohydantoin, namely the non-pharmacophoric part. All the new compounds exhibit high potency for the 5-HT1A receptor; however, affinities for the α1 receptor are high for compounds 2a–l while compounds 3a–f are selective over this adrenergic receptor. On the other hand, differences in logP do not notably affect the Ki values for the above receptors.

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