Arylpiperazinylalkylpyridazinones and analogues as potent and orally active antinociceptive agents: synthesis and studies on mechanism of action.
A number of arylpiperazinylalkylpyridazinones structurally related to the previously described lead A (5-{[4-(3-chlorophenyl)piperazin-1-yl]-propyl}-3-methyl-7-phenylisossazolo[4,5-d]pyridazin-4-(5H)-one) were synthesized and tested for their analgesic activity. Many of the tested molecules, at the dose of 20 mg kg-1 p.o., showed high antinociceptive activity, in particular, compounds 5a, 11c, 15a, 21 and 22, which were able to reduce the number of abdominal constrictions by more than 50% in writhing test. The pharmacological investigation of lead A led us to clarify the mechanism of action of this compound, showing that it carries out its analgesic action through the inhibition of reuptake of noradrenaline. The antinociception of some of the most interesting new molecules was completely prevented by pretreatment with alpha2-antagonist yohimbine, suggesting the involvement of alpha2-adrenoceptors, as with prototype A.
Cesari
Nicoletta
N
Dipartimento di Scienze Farmaceutiche, via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
Biancalani
Claudio
C
Vergelli
Claudia
C
Dal Piaz
Vittorio
V
Graziano
Alessia
A
Biagini
Pierfrancesco
P
Ghelardini
Carla
C
Galeotti
Nicoletta
N
Giovannoni
Maria Paola
MP
D000009:Abdominal Muscles / Q000187:drug effects; D015746:Abdominal Pain / Q000139:chemically induced / Q000188:drug therapy; D000284:Administration, Oral; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D009638:Norepinephrine; D011724:Pyridazines; D017367:Selective Serotonin Reuptake Inhibitors; D015016:Yohimbine