title: Synthesis and pharmacological evaluation in mice of new non-classical antinociceptive agents, 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones.
abstract: Several 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones have been synthesized and tested for analgesic activity in a visceral pain model (phenylbenzoquinone-induced writhing test = PBQ test). A good correlation has been found between the antinociceptive effects of drugs and both their lipophilic and steric properties. The most active derivatives 5c and 5f, with intraperitoneal ED50 values of 10.5 and 10.3 mg kg-1 respectively, were more extensively investigated by evaluating their analgesic activity in a somatosensory pain model (hot plate test), as well as their sedative properties. Furthermore, naloxone suppressed the effect of 5c and 5f in the PBQ test, though these derivatives were ineffective to potentiate morphine analgesia. Pretreatment with yohimbine did not significantly attenuate the analgesic effects of 5c and 5f. In addition, pretreatment with 5-hydroxytryptophan associated with carbidopa also failed to potentiate the antinociceptive effects of 5c and 5f. So, a part of the analgesic activity of 5c and 5f seems to be related to an opioidergic mechanisms, especially at the mu receptor level. Molecular modeling studies performed on the opiate drug morphine and on the most stable conformer of 5f showed structural similarities between these two molecules.
authors.affiliation: Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Clermont-Ferrand, France.
authors.forename: M
authors.initials: M
authors.lastname: Bebot
authors.forename: P
authors.initials: P
authors.lastname: Coudert
authors.forename: C
authors.initials: C
authors.lastname: Rubat
authors.forename: D
authors.initials: D
authors.lastname: Vallee-Goyet
authors.forename: D
authors.initials: D
authors.lastname: Gardette
authors.forename: S
authors.initials: S
authors.lastname: Mavel
authors.forename: E
authors.initials: E
authors.lastname: Albuisson
authors.forename: J
authors.initials: J
authors.lastname: Couquelet
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D055672:Static Electricity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D016227:Benzoquinones; D010078:Oxazines; D010879:Piperazines; C029322:phenylbenzoquinone