title: Synthesis, biological evaluation, and pharmacophore generation of new pyridazinone derivatives with affinity toward alpha(1)- and alpha(2)-adrenoceptors.
abstract: A series of new pyridazin-3(2H)-one derivatives (3 and 4) were evaluated for their in vitro affinity toward both alpha(1)- and alpha(2)-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the alpha(1)-adrenoceptor, with K(i) values in the low nanomolar range. The polymethylene chain constituting the spacer between the furoylpiperazinyl pyridazinone and the arylpiperazine moiety was shown to influence the affinity and selectivity of these compounds. Particularly, a gradual increase in affinity was observed by lengthening the polymethylene chain up to a maximum of seven carbon atoms. In addition, compound 3k, characterized by a very interesting alpha(1)-AR affinity (1.9 nM), was also shown to be a highly selective alpha(1)-AR antagonist, the affinity ratio for alpha(2)- and alpha(1)-adrenoceptors being 274. To gain insight into the structural features required for alpha(1) antagonist activity, the pyridazinone derivatives were submitted to a pharmacophore generation procedure using the program Catalyst. The resulting pharmacophore model showed high correlation and predictive power. It also rationalized the relationships between structural properties and biological data of, and external to, the pyridazinone class.
authors.affiliation: Istituto di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Barbaro
authors.forename: L
authors.initials: L
authors.lastname: Betti
authors.forename: M
authors.initials: M
authors.lastname: Botta
authors.forename: F
authors.initials: F
authors.lastname: Corelli
authors.forename: G
authors.initials: G
authors.lastname: Giannaccini
authors.forename: L
authors.initials: L
authors.lastname: Maccari
authors.forename: F
authors.initials: F
authors.lastname: Manetti
authors.forename: G
authors.initials: G
authors.lastname: Strappaghetti
authors.forename: S
authors.initials: S
authors.lastname: Corsano
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016208:Databases, Factual; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D011224:Prazosin / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D008024:Ligands; D011724:Pyridazines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011224:Prazosin