title: Acute and chronic antiparkinsonian effects of the novel nociceptin/orphanin FQ receptor antagonist NiK-21273 in comparison with SB-612111.
abstract: OBJECTIVE
  Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonists have been proposed as a novel therapeutic approach to Parkinson's disease. Main limitations of previous studies were the use of structurally similar compounds and the evaluation of their acute effects only. We report here on the acute and long-term antiparkinsonian effects of the novel compound 2-[3-[4-(2-chloro-6-fluoro-phenyl)-piperidin-1-ylmethyl]-2-(morpholine-4-carbonyl)-indol-1-yl]-acetamide (NiK-21273) in comparison with the potent and selective NOP receptor antagonist SB-612111.
  
  
  METHODS
  Basic pharmacological properties of NiK-21273 were studied in cell lines and isolated tissues (mouse and rat vas deferens). Antiparkinsonian effects were studied in reserpinized mice and 6-hydroxydopamine hemilesioned rats under both acute and chronic administration protocols.
  
  
  RESULTS
  In vitro, NiK-21273 behaved as a potent (pA(2) 7.7) and selective NOP receptor antagonist. In vivo, it reduced hypokinesia in reserpinized mice at 0.1 and 1 but not 10 mg·kg(-1), whereas SB-612111 (0.01-1 mg·kg(-1)) provided a dose-dependent antiparkinsonian effect. NiK-21273 ameliorated motor performance in 6-hydroxydopamine hemilesioned rats at 0.5 and 5 but not 15 mg·kg(-1). SB-612111 replicated these effects in the 0.01-1 mg·kg(-1) range without loss of efficacy. Both antagonists synergized with L-DOPA at subthreshold doses. Chronic administration of NiK-21273 provided delayed improvement in baseline activity at 0.5 and 1.5 mg·kg(-1), although tolerance to the higher dose was observed. Conversely, SB-612111 (1 mg·kg(-1)) maintained its effects over time without modifying baseline activity.
  
  
  CONCLUSIONS
  NOP receptor antagonists provide motor benefit in parkinsonism models although the 'therapeutic' window and long-term effects may vary between compounds.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marti
authors.forename: F
authors.initials: F
authors.lastname: Mela
authors.forename: M
authors.initials: M
authors.lastname: Budri
authors.forename: M
authors.initials: M
authors.lastname: Volta
authors.forename: D
authors.initials: D
authors.lastname: Malfacini
authors.forename: S
authors.initials: S
authors.lastname: Molinari
authors.forename: N T
authors.initials: NT
authors.lastname: Zaveri
authors.forename: S
authors.initials: S
authors.lastname: Ronzoni
authors.forename: P
authors.initials: P
authors.lastname: Petrillo
authors.forename: G
authors.initials: G
authors.lastname: Calò
authors.forename: M
authors.initials: M
authors.lastname: Morari
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003508:Cycloheptanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009292:Narcotic Antagonists; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000235:genetics; D012110:Reserpine / Q000494:pharmacology; D045442:Rotarod Performance Test; D014162:Transfection; D014649:Vas Deferens / Q000187:drug effects; D000094942:Nociceptin Receptor
chemical_list: C582145:2-(3-(4-(2-chloro-6-fluoro-phenyl)-piperidin-1-ylmethyl)-2-(morpholine-4-carbonyl)-indol-1-yl)-acetamide; D000978:Antiparkinson Agents; D003508:Cycloheptanes; D007211:Indoles; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; D012110:Reserpine; D002118:Calcium; D000094942:Nociceptin Receptor