4-amino-5-substituted-3(2H)-pyridazinones as orally active antinociceptive agents: synthesis and studies on the mechanism of action.
A number of 4-amino-5-vinylpyridazinones and 4-amino-5-heterocyclic-pyridazinones were synthesized and tested for their analgesic activity. Many of these compounds, tested at doses of 3-20 mg kg-1 po, showed good antinociceptive activity, reducing by more than 50% the number of writhes with respect to controls. Compounds 16c, 19a, 20a, and 28 were the most potent of the series because they were able to induce a potent antinociceptive effect at a dose of 3 mg kg-1 po. None of the active compounds at the analgesic dose provoked any visible change in normal behavior, as demonstrated in the rotarod test. Studies on the mechanism of action showed that the analgesia induced by the active compounds was completely prevented by pretreatment with the alpha2-antagonist yohimbine, suggesting an involvement of alpha2-adrenoceptors. Further investigation demonstrated an indirect activation of the noradrenergic system through an amplification of noradrenaline release.
Giovannoni
Maria Paola
MP
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy. mariapaola.giovannoni@unifi.it
Cesari
Nicoletta
N
Vergelli
Claudia
C
Graziano
Alessia
A
Biancalani
Claudio
C
Biagini
Pierfrancesco
P
Ghelardini
Carla
C
Vivoli
Elisa
E
Dal Piaz
Vittorio
V
D000284:Administration, Oral; D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D008297:Male; D051379:Mice; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism; D010147:Pain Measurement; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D015016:Yohimbine / Q000494:pharmacology
D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D011724:Pyridazines; D015016:Yohimbine; D009638:Norepinephrine