title: Analgesic activity and pharmacological characterization of N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl] propenamide, a new opioid agonist acting peripherally.
abstract: We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M.I., Callado, L.F., Cano, C., Goya, P., Jagerovic, N. 2002. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71, 1023-1034]. One of them, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (IQMF-4), showed an interesting antinociceptive activity. Intraperitoneally (i.p.) administered, it was as effective as fentanyl or morphine, being less potent than fentanyl but more so than morphine. The aim of the present work was to evaluate its antinociceptive effect by different routes of administration, using the hot plate test, and to investigate possible side effects, such as tolerance and withdrawal, in vitro, using the myenteric plexus-longitudinal muscle strip preparation from guinea pig ileum, and in vivo, using the hot plate test. IQMF-4 was more potent than morphine when administered per os (p.o.), but less potent when administered intracerebroventricularly (i.c.v.). By both routes, fentanyl is more potent that IQMF-4. When IQMF-4 was administered i.p., naloxone methiodide, a peripherally acting antagonist, was able to completely block its antinociceptive effect, whereas, after i.c.v. administration, the blockade was only partial. An interesting feature of the new compound is that it induces tolerance in vitro but not in vivo. Moreover, though in vitro withdrawal was not different from fentanyl or morphine, in vivo withdrawal symptoms were significantly less frequent in mice treated with IQMF-4 than in those treated with morphine or fentanyl. Although more assays are required, these results show that IQMF-4 appears to be a potent analgesic compound with an interesting peripheral component, and reduced ability to induce dependence.
authors.affiliation: Unidad de Farmacología, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Spain. carlos.goicoeche@urjc.es
authors.forename: Carlos
authors.initials: C
authors.lastname: Goicoechea
authors.forename: Eva
authors.initials: E
authors.lastname: Sánchez
authors.forename: Carolina
authors.initials: C
authors.lastname: Cano
authors.forename: Nadine
authors.initials: N
authors.lastname: Jagerovic
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Martín
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005283:Fentanyl / Q000494:pharmacology; D006168:Guinea Pigs; D006358:Hot Temperature; D007082:Ileum / Q000187:drug effects / Q000294:innervation; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000209:etiology / Q000517:prevention & control; D010146:Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D011407:Propane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; C532943:N-(1-phenylpyrazol-3-yl)-N-(1-(2-phenethyl)-4-piperidyl) propenamide; D009292:Narcotic Antagonists; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; D009270:Naloxone; C041269:N-methylnaloxone; D009020:Morphine; D011407:Propane; D005283:Fentanyl