Synthesis, anticonvulsant activity and 5-HT1A, 5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-alkyl] derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione

Abstract

The synthesis, physicochemical and pharmacological properties of new N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane- (8a-c, 10a-d) and [4.5]decane-1,3-dione (9a-c, 11a-d) derivatives were described. The antiepileptic effects of those compounds were examined by a maximal electroshock (MES) and a pentylenetetrazole (sc. PTZ) tests, and their neurotoxicity was determined using a rota-rod test. Compounds 8c, 9c, 10c, d, 11c, d with a CF3 group at the 3-position of the 4-arylpiperazine fragment exhibited anti-seizure properties in the MES model; in contrast, their 2-CH3 and 2-OCH3 analogues were inactive in both the tests used. Moreover, since the investigated compounds belong to the class of long-chain arylpiperazines, their serotonin 5-HT1A and 5-HT2A receptor affinity was determined. The relationship between the length of alkylene spacer and 5-HT1A/5-HT2A receptor activity was observed. Compounds with an ethylene and a propylene bridge (10a-d and 11a-d) were 3-80-fold more potent (Ki ranged from 3.1 to 94 nM for 5-HT1A and 32-465 nM for 5-HT2A) than their methylene analogues (8a-c and 9a-c; Ki ranged from 81 to 370 nM for 5-HT1A and 126-1370 nM for 5-HT2A). The highest 5-HT1A receptor affinity was displayed by 2-OCH3 and 3-CF3 phenyl derivatives (10b, 11b: Ki = 6.8 and 5.7 nM, respectively, and 10c, 11c: Ki = 6.0 and 3.1 nM, respectively), while in the case of 5-HT2A receptor the highest affinity was observed for the 3-CF3 phenyl derivatives 10c, d, 11c, d (Ki ranged from 32 to 86 nM). © 2006 Elsevier SAS. All rights reserved.