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Synthesis and In Vitro Pharmacological Evaluation of Novel 2‐Hydroxypropyl‐4‐arylpiperazine Derivatives as Serotoninergic Ligands
Author(s) -
Fiorino Ferdinando,
Magli Elisa,
Severino Beatrice,
Corvino Angela,
Ciano Antonio,
Perissutti Elisa,
Frecentese Francesco,
Massarelli Paola,
Nencini Cristina,
Santagada Vincenzo,
Caliendo Giuseppe
Publication year - 2014
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201400174
Subject(s) - chemistry , receptor , piperazine , stereochemistry , 5 ht receptor , serotonergic , dopaminergic , affinities , serotonin , chemical synthesis , in vitro , biochemistry , dopamine , organic chemistry , biology , endocrinology
This paper reports the synthesis of new norbornene and exo‐ N ‐hydroxy‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2,3‐dicarboximide derivatives and their binding to the 5‐HT 1A , 5‐HT 2A , and 5‐HT 2C receptors, in order to identify selective ligands for these 5‐hydroxytryptamine (5‐HT, serotonine) receptor subtypes. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4‐substituted piperazine) known to be critical for affinity to 5‐HT 1A receptors and the proper selection of substituents led to compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected and further evaluated for their binding affinities to D 1 , D 2 dopaminergic and α 1 , α 2 adrenergic receptors. 4‐[3‐[4‐(2‐Furoyl)piperazin‐1‐yl]propoxy‐2‐ol]‐4‐aza‐tricyclo[5.2.1.02,6]dec‐8‐ene‐3,5‐dione 3e with K i = 5.04 ± 0.227 nM was the most active and selective derivative for the 5‐HT 2C receptor with respect to other serotonin receptors, and the most selective derivative versus dopaminergic and adrenergic receptors.