RESUMEN
New 4-(diphenylmethyl)-1-piperazine derivatives with a terminal heteroaryl or cycloalkyl amide fragment were synthesized and evaluated for their antihistaminic, anticholinergic and antiallergic activities. Tested compounds were found to be moderate to potent in vitro (guinea-pig ileum) histamine H(1)-receptor antagonists. Derivatives with a four methylene chain (1e-1h) were as potent in vivo (capillary permeability in rats) as cetirizine; the heteroaryl derivatives 1e and 1h were found to be the most active agents. These compounds displayed only weak in vitro (guinea-pig ileum) muscarinic M(3)-receptor antagonist activity. Compounds 1e and 1g were about 100 times more potent than ketotifen in preventing the compound 48/80-induced histamine release from rat peritoneal mast cells. Derivatives 1e, 1f and 1h did not modify the spontaneous motor activity in rats at 100 mg/kg po. Compound 1e has been selected for further studies.
RESUMEN
New 2-(methoxyphenyl)piperazine derivatives 1 and 2 containing a terminal heteroaryl or cycloalkyl amide fragment were prepared and their 5-HT1A affinities evaluated by radioligand binding assays. The influence of the alkyl chain length or the amide group on affinity was evaluated. A four-carbon chain appears to be optimal when the amide fragment is a heteroaryl group. Derivatives with a cycloalkyl moiety displayed maximum affinity in the two methylene chain series. Electronic distribution within the amide region seems to have an influence on affinity in heteroaryl derivatives. Replacement of the heteroaryl moiety by a cycloalkyl group led to compounds with enhanced affinity. Increasing the lipophilicity of the cycloalkyl derivatives by annelation and/or saturation increased their affinity for the 5-HT1A sites. Compounds with cis-bicyclo[3.3.0]octane (2a, 2c), norbornane (2f, 2g), and norbornene (2h, 2i) groups bind at 5-HT1A sites with 2-10-fold higher affinity than NAN-190. Antagonist activity at alpha 1-adrenergic receptors was evaluated for compounds with high affinity at 5-HT1A sites. Compounds 2a, 2c, 2f, 2g, and 2h strongly bind (Ki = 0.12-0.63 nM) at 5-HT1A receptors and are devoid of antagonist activity at alpha 1-adrenergic receptors.