Title of article :
Synthesis, biological activity, QSAR and QSPR study of 2-aminobenzimidazole derivatives as potent H3-antagonists Original Research Article
Author/Authors :
Marco Mor، نويسنده , , Fabrizio Bordi، نويسنده , , Claudia Silva، نويسنده , , Silvia Rivara، نويسنده , , Valentina Zuliani، نويسنده , , Federica Vacondio، نويسنده , , Mirko Rivara، نويسنده , , Elisabetta Barocelli، نويسنده , , Simona Bertoni، نويسنده , , Vigilio Ballabeni، نويسنده , , Francesca Magnanini، نويسنده , , Mariannina Impicciatore، نويسنده , , Pier Vincenzo Plazzi، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2004
Abstract :
We report the design, synthesis, QSPR and QSAR of a new class of H3-antagonists, having a 2-aminobenzimidazole moiety connected to the 4(5) position of an imidazole ring through di- or tri-methylene chains. Eleven substituents, selected by experimental design to obtain broad and non-correlated variation in their lipophilic, electronic and steric properties, were introduced at the 5(6) position of the benzimidazole nucleus. The compounds were tested for their H3-receptor affinity, by displacement of [3H]-(R)-α-methylhistamine ([3H]-RAMHA) binding to rat brain membranes (pKi), for intrinsic activity, evaluating their effect on [35S]GTPγS binding to rat brain membranes, and for H3-antagonist potency, on electrically stimulated guinea-pig ileum (pKB). The pKi values of the derivatives with longer chain (5a–k) ranged over 2 orders of magnitude, with the 5(6)-methoxy derivative 5d endowed with sub-nanomolar affinity (pKi=9.37). The series having two methylene groups in the chain spacer (4a–k), showing a small variation in affinity, revealed to be somewhat insensitive to ring substitution. Lipophilicity (log P) and basicity (pKa) of the newly synthesized compounds were measured and related to receptor affinity in a QSAR study. Multiple regression analysis (MRA) showed an approximate parabolic dependence of pKi on log P, while an additional electronic effect of the substituents on benzimidazole tautomerism is suspected.
Keywords :
2-Aminobenzimidazole , Histamine , QSAR , H3-receptor antagonists
Journal title :
Bioorganic and Medicinal Chemistry
Journal title :
Bioorganic and Medicinal Chemistry