title: Spirobutenolides substituted by arylpiperazinyl-carbonyl moieties. Synthesis and antinociceptive properties.
abstract: The synthesis and spectral data of some new cyclohexane-2-spiro-[2,5-dihydro-3-(N-arylpiperazin-1-yl-carbonyl) -4-methyl- 5-oxo]furanes are reported. These compounds were subjected to pharmacological tests for evaluation of antinociceptive effects and interactions with opioidergic and monoaminergic systems. With respective ED50 values of 116.4 and 87.0 mg/kg i.p., derivatives 2b and 2e were the most active spirobutenolides in the phenylbenzoquinone-induced writhing test (PBQ-test) without neurotoxic effects. They potentiated morphine analgesia and were also active at the dose of 150 mg/kg i.p. in the hot plate test while they exhibited sedative effects from the dose of 100 mg/kg i.p. In addition, 2b and 2e analgesia was antagonized by naloxone, then again potentiated by 5-hydroxytryptophan associated to carbidopa in the PBQ-test, demonstrating involvement of opioidergic and serotonergic pathways in the analgesic properties of both compounds. Furthermore, antinociceptive effects of 2e were attenuated by oral administration of yohimbine suggesting that its analgesic activity was also partly related to a noradrenergic mechanism.
authors.affiliation: Groupe de Recherche en Pharmacochimie-Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: F
authors.initials: F
authors.lastname: Bois
authors.forename: S
authors.initials: S
authors.lastname: Moreau
authors.forename: P
authors.initials: P
authors.lastname: Coudert
authors.forename: C
authors.initials: C
authors.lastname: Rubat
authors.forename: J
authors.initials: J
authors.lastname: Couquelet
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones; D004357:Drug Synergism; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D000701:Analgesics, Opioid; D016227:Benzoquinones; D005663:Furans; D009292:Narcotic Antagonists; D013141:Spiro Compounds; D015016:Yohimbine; C029322:phenylbenzoquinone; D009270:Naloxone; D009020:Morphine; D006916:5-Hydroxytryptophan