title: Isoxazolo-[3,4-d]-pyridazin-7-(6H)-ones and their corresponding 4,5-disubstituted-3-(2H)-pyridazinone analogues as new substrates for alpha1-adrenoceptor selective antagonists: synthesis, modeling, and binding studies.
abstract: A series of phenylpiperazinylalkyl moieties were attached to monocyclic or bicyclic substituted pyridazinones and the new compounds tested for their affinity towards alpha1-adrenoceptor and its alpha1a, alpha1b and alpha1d subtypes, as well as serotonin 5-HT1A receptor. Several analogues (5, 6, 9, and 10) showed remarkable potency and selectivity towards alpha1a, and alpha1d with respect to alpha1b subtype. None of the test compounds exhibited significant affinity for 5-HT1A receptor. Finally, on the basis of the alpha1-AR subtypes 3D models recently proposed, we have elaborated theoretical interaction models for the new compounds. The theoretical study allowed us to predict the affinity of the new compounds as well as to infer the structural/dynamics determinants of their interaction with the three alpha1-AR subtypes.
authors.affiliation: Ist. Chimica Farmaceutica e Tossicologica, Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Montesano
authors.forename: D
authors.initials: D
authors.lastname: Barlocco
authors.forename: V
authors.initials: V
authors.lastname: Dal Piaz
authors.forename: A
authors.initials: A
authors.lastname: Leonardi
authors.forename: E
authors.initials: E
authors.lastname: Poggesi
authors.forename: F
authors.initials: F
authors.lastname: Fanelli
authors.forename: P G
authors.initials: PG
authors.lastname: De Benedetti
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C547713:ADRA1A protein, human; C547716:ADRA1B protein, human; C547719:ADRA1D protein, human; D000317:Adrenergic alpha-Antagonists; D011724:Pyridazines; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins