Synthesis, anticonvulsant activity and 5-HT 1A, 5-HT 2A 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 CF 3 group at the 3-position of the 4-arylpiperazine fragment exhibited anti-seizure properties in the MES model; in contrast, their 2-CH 3 and 2-OCH 3 analogues were inactive in both the tests used. Moreover, since the investigated compounds belong to the class of long-chain arylpiperazines, their serotonin 5-HT 1A and 5-HT 2A receptor affinity was determined. The relationship between the length of alkylene spacer and 5-HT 1A/5-HT 2A receptor activity was observed. Compounds with an ethylene and a propylene bridge ( 10a– d and 11a– d) were 3–80-fold more potent ( K i ranged from 3.1 to 94 nM for 5-HT 1A and 32–465 nM for 5-HT 2A) than their methylene analogues ( 8a– c and 9a– c; K i ranged from 81 to 370 nM for 5-HT 1A and 126–1370 nM for 5-HT 2A). The highest 5-HT 1A receptor affinity was displayed by 2-OCH 3 and 3-CF 3 phenyl derivatives ( 10b, 11b: K i = 6.8 and 5.7 nM, respectively, and 10c, 11c: K i = 6.0 and 3.1 nM, respectively), while in the case of 5-HT 2A receptor the highest affinity was observed for the 3-CF 3 phenyl derivatives 10c, d, 11c, d ( K i ranged from 32 to 86 nM).