title: Synthesis and three-dimensional quantitative structure-activity relationship analysis of H3 receptor antagonists containing a neutral heterocyclic polar group.
abstract: Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H(3) receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.
authors.affiliation: Università degli Studi di Parma, Parma, Italy. silvia.rivara@unipr.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
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: Valentina
authors.initials: V
authors.lastname: Zuliani
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Morini
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.forename: Bernard
authors.initials: B
authors.lastname: Testa
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D006571:Heterocyclic Compounds; D006633:Histamine Antagonists; D007093:Imidazoles; D018100:Receptors, Histamine H3; D013844:Thiazoles