Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

[1]  W. Martin,et al.  A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships. , 2013, Bioorganic & medicinal chemistry letters.

[2]  R. Depoortère,et al.  Milnacipran is active in models of irritable bowel syndrome and abdominal visceral pain in rodents. , 2011, European journal of pharmacology.

[3]  Howard S. Smith,et al.  Journal of Central Nervous System Disease Duloxetine: a Review of Its Safety and Efficacy in the Management of Fibromyalgia Syndrome , 2022 .

[4]  P. Masand,et al.  Serotonin-Norepinephrine Reuptake Inhibitors for Pain Control: Premise and Promise , 2009, Current neuropharmacology.

[5]  J. Mendiola,et al.  Enzymatic Resolution of N -Substituted--prolines , 2009 .

[6]  B. Eastwood,et al.  Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: Evidence for synergism between serotonergic and noradrenergic reuptake inhibition , 2006, Neuropharmacology.

[7]  Gordon Campbell,et al.  Discovery of novel and selective tertiary alcohol containing inhibitors of the norepinephrine transporter. , 2006, Bioorganic & medicinal chemistry letters.

[8]  S. Stahl,et al.  SNRIs: The Pharmacology, Clinical Efficacy, and Tolerability in Comparison with Other Classes of Antidepressants , 2005, CNS Spectrums.

[9]  L. Arendt-Nielsen,et al.  The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study , 2005, European journal of pain.

[10]  M. Walter.  Monoamine reuptake inhibitors: highlights of recent research developments , 2005 .

[11]  D. McKinzie,et al.  Pharmacologic Interactions between the Muscarinic Cholinergic and Dopaminergic Systems in the Modulation of Prepulse Inhibition in Rats , 2005, Journal of Pharmacology and Experimental Therapeutics.

[12]  H. Shannon,et al.  Efficacy of Duloxetine, a Potent and Balanced Serotonergic and Noradrenergic Reuptake Inhibitor, in Inflammatory and Acute Pain Models in Rodents , 2005, Journal of Pharmacology and Experimental Therapeutics.

[13]  S. Iyengar,et al.  Efficacy of Duloxetine, a Potent and Balanced Serotonin-Norepinephrine Reuptake Inhibitor in Persistent Pain Models in Rats , 2004, Journal of Pharmacology and Experimental Therapeutics.

[14]  J. Zajecka,et al.  SNRIs in the management of acute major depressive disorder. , 2004, The Journal of clinical psychiatry.

[15]  S. Houle,et al.  Novel Radiotracers for Imaging the Serotonin Transporter by Positron Emission Tomography: Synthesis, Radiosynthesis, and in Vitro and ex Vivo Evaluation of (11)C-Labeled 2-(Phenylthio)araalkylamines. , 2000, Journal of medicinal chemistry.

[16]  S. Houle,et al.  Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of (11)C-labeled 2-(phenylthio)araalkylamines. , 2000, Journal of medicinal chemistry.

[17]  W. Willis.  Central nervous system mechanisms for pain modulation. , 1985, Applied neurophysiology.