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Obniska J, Kolaczkowski M, Bojarski AJ, Duszynska B: 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. Eur J Med Chem. 2006 Jul;41(7):874-81. Epub 2006 Apr 4.
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). |
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