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 R2-antagonist yohimbine, suggesting the involvement of R2-adrenoceptors, as with prototype A.