title: Toward the identification of neuroprotective agents: g-scale synthesis, pharmacokinetic evaluation and CNS distribution of (R)-RC-33, a promising SIGMA1 receptor agonist.
abstract: OBJECTIVE
  Nowadays, there is a great interest in the therapeutic potential of sigma1 receptor ligands for treating different CNS pathologies. Our previous investigations led to identify (R)-RC-33 as a potent and selective S1R agonist.
  
  
  RESULTS
  Herein, we report the gram-scale synthesis, pharmacokinetic profile and CNS distribution of (R)-RC-33 in the mouse to determine the most suitable dosage schedule for in vivo administration. For comparative purposes, the same experiments were also performed with PRE-084, the most widely used S1R agonist commonly in pharmacological experiments.
  
  
  CONCLUSIONS
  (R)-RC-33 shows a similar pharmacokinetic profile and a better CNS distribution when compared with PRE-084.
  
  
  CONCLUSIONS
  (R)-RC-33 may be a promising candidate for in vivo studies in animal models of neurodegenerative diseases.
authors.affiliation: Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia-I, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Marra
authors.affiliation: Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia-I, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi 19, 20133 Milano-I, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pignataro
authors.affiliation: Aphad S.r.l., Via della Resistenza 65, 20090 Buccinasco Milan-I, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.affiliation: Experimental Neurology Unit, Department of Surgery & Translational Medicine & Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, 20900 Monza-I, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Canta
authors.affiliation: Experimental Neurology Unit, Department of Surgery & Translational Medicine & Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, 20900 Monza-I, Italy.
authors.forename: Norberto
authors.initials: N
authors.lastname: Oggioni
authors.affiliation: Experimental Neurology Unit, Department of Surgery & Translational Medicine & Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, 20900 Monza-I, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Malacrida
authors.affiliation: Department of Neurorehabilitation Sciences, Casa Cura Policlinico (CCP), via Dezza 48, 20144 Milan-I, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Corbo
authors.affiliation: Experimental Neurology Unit, Department of Surgery & Translational Medicine & Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, 20900 Monza-I, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.affiliation: Department of Biology & Biotechnology "L. Spallanzani", University of Pavia, Via Ferrata 9, 27100 Pavia-I, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Peviani
authors.affiliation: Department of Biology & Biotechnology "L. Spallanzani", University of Pavia, Via Ferrata 9, 27100 Pavia-I, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Curti
authors.affiliation: Aphad S.r.l., Via della Resistenza 65, 20090 Buccinasco Milan-I, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.affiliation: Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia-I, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Collina
mesh_terms: D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002493:Central Nervous System Diseases / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017480:Receptors, sigma / Q000819:agonists*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D001713:Biphenyl Compounds; D009025:Morpholines; D018696:Neuroprotective Agents; D010880:Piperidines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C584299:1-(3-biphenyl-4-ylbutyl)piperidine; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
keywords: CNS distribution; Parkinson's disease; S1R agonist; amyotrophic lateral sclerosis; multiple sclerosis; neurological disorders; pharmacokinetic profile