Further studies on arylpiperazinyl alkyl pyridazinones: discovery of an exceptionally potent, orally active, antinociceptive agent in thermally induced pain.
A number of pyridazinone derivatives bearing an arylpiperazinylalkyl chain were synthesized and tested icv in a model of acute nociception induced by thermal stimuli in mice (tail flick). The most interesting and potent compound in this series was 6a, which showed an ED(50) = 3.5 microg, a value about 3-fold higher with respect to morphine by the same route of administration. When administered per os, 6a was 4-fold more potent than morphine in the same test, suggesting a significant bioavailability. The same compound also showed high potency in the hot plate test. The antinociceptive effect of 6a was completely reversed by pretreatment with yohimbine both in the hot plate test and in the tail flick test. This demonstrated the involvement of the adrenergic system, which was confirmed by in vitro radioligand binding studies.
Dipartimento di Scienze Farmaceutiche, via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
Claudio
C
Biancalani
Maria Paola
MP
Giovannoni
Stefano
S
Pieretti
Nicoletta
N
Cesari
Alessia
A
Graziano
Claudia
C
Vergelli
Agostino
A
Cilibrizzi
Amalia
A
Di Gianuario
Mariantonella
M
Colucci
Giorgina
G
Mangano
Beatrice
B
Garrone
Lorenzo
L
Polenzani
Vittorio
V
Dal Piaz
D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D006358:Hot Temperature / Q000009:adverse effects*; D006801:Humans; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011724:Pyridazines / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011941:Receptors, Adrenergic / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D010879:Piperazines; D011724:Pyridazines; D011941:Receptors, Adrenergic; D000077489:Piperazine; C062482:pyridazine