Alpha1-adrenoceptor antagonists. 6. Structural optimization of pyridazinone-arylpiperazines. Study of the influence on affinity and selectivity of cyclic substituents at the pyridazinone ring and alkoxy groups at the arylpiperazine moiety.
In continuing our search for selective alpha(1)-adrenoceptor (AR) antagonists, we have synthesized new alkoxyarylpiperazinylalkylpyridazinone derivatives. The new compounds were tested for their affinity toward alpha(1)- and alpha(2)-AR and toward the 5-HT(1A) receptor. alpha(1)-AR affinity data are in the subnanomolar range, with 3 showing an affinity of 0.052 nM, about 5-fold higher than prazosin. None of the studied compounds was found to be alpha(1)/alpha(2) selective, but 8 showed an interesting 5-HT(1A)/alpha(1) affinity ratio of 119.
Betti
Laura
L
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Corelli
Federico
F
Floridi
Monia
M
Giannaccini
Gino
G
Maccari
Laura
L
Manetti
Fabrizio
F
Strappaghetti
Giovannella
G
Botta
Maurizio
M
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D013329:Structure-Activity Relationship
D000317:Adrenergic alpha-Antagonists; D008024:Ligands; D010879:Piperazines; D011724:Pyridazines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1