title: Synthesis, biological activity, QSAR and QSPR study of 2-aminobenzimidazole derivatives as potent H3-antagonists.
abstract: We report the design, synthesis, QSPR and QSAR of a new class of H(3)-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 H(3)-receptor affinity, by displacement of [(3)H]-(R)-alpha-methylhistamine ([(3)H]-RAMHA) binding to rat brain membranes (pK(i)), for intrinsic activity, evaluating their effect on [(35)S]GTPgammaS binding to rat brain membranes, and for H(3)-antagonist potency, on electrically stimulated guinea-pig ileum (pK(B)). The pK(i) 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 (pK(i)=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 (pK(a)) 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 pK(i) on log P, while an additional electronic effect of the substituents on benzimidazole tautomerism is suspected.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43100 Parma, Italy. marco.mor@unipr.it
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bordi
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuliani
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.forename: Francesca
authors.initials: F
authors.lastname: Magnanini
authors.forename: Mariannina
authors.initials: M
authors.lastname: Impicciatore
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008761:Methylhistamines / Q000494:pharmacology; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D006633:Histamine Antagonists; D008761:Methylhistamines; D018100:Receptors, Histamine H3; C069357:alpha-methylhistamine; C027391:2-aminobenzimidazole