Isoxazolo-[3,4-d]-pyridazin-7-(6H)-ones and their Corresponding 4,5-Disubstituted-3-(2H)-pyridazinone Analogues as New Substrates for α1-Adrenoceptor Selective Antagonists: Synthesis, Modeling, and Binding Studies Original Research Article

A series of phenylpiperazinylalkyl moieties were attached to monocyclic or bicyclic substituted pyridazinones and the new compounds tested for their affinity towards α1-adrenoceptor and its α1a, α1b and α1d subtypes, as well as serotonin 5-HT1A receptor. Several analogues (5, 6, 9, and 10) showed remarkable potency and selectivity towards α1a, and α1d with respect to α1b subtype. None of the test compounds exhibited significant affinity for 5-HT1A receptor. Finally, on the basis of the α1-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 α1-AR subtypes.