Design and synthesis of potential dual NK 1 /NK 3 receptor antagonists Stephen Hanessian a,⇑ , Vincent Babonneau a , Nicolas Boyer a,  , Clotilde Mannoury la Cour b , Mark J. Millan b , Guillaume De Nanteuil c a Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, Que. H3C 3J7, Canada b Department of Psychopharmacology, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy/Seine, France c Neuroscience Chemistry Research Unit, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France article info Article history: Received 22 November 2013 Revised 4 December 2013 Accepted 9 December 2013 Available online 15 December 2013 Keywords: Schizophrenia Neurokinin receptors Peptidomimetic NK 1 /NK 3 receptor antagonists abstract The tachykinin NK 1 and NK 3 receptors are a novel drug target for schizophrenia in order to treat not only the positive and cognitive symptoms, but also the associated co-morbid depression and sleep disturbances associated with the disease. A novel class of peptidomimetic derivatives based on a versatile phenylglycine central core was synthesized and tested in vitro as dual NK 1 /NK 3 receptor antagonists. From this series emerged compounds with good NK 1 receptor affinity, although only modest dual NK 1 /NK 3 receptor affinity was observed with one of these analogs. Ó 2013 Elsevier Ltd. All rights reserved. Schizophrenia is a severe, lifelong, devastating mental disorder that affects approximately 1% of the world population and is among the world’s top ten causes of long-term disability. 1 Clinical symptoms are characterized by the presence of positive, negative and mood symptoms, as well as cognitive impairment. Current antipsychotic therapies (D 2 /5-HT 2A receptor antagonists) are effec- tive against positive symptoms but have a poor efficacy in the treatment of negative and cognitive symptoms. Furthermore, these drugs suffer from serious side effects and a high non-responder rate. 2 Mammalian tachykinins (also known as neurokinins, NK) are a family of structurally related neuropeptides which are mainly distributed in the central (CNS) and peripheral (PNS) nervous sys- tems. 3 This group of endogenous neuromodulators is characterized by a common C-terminal sequence: Phe–X–Gly–Leu–Met–NH 2 where X is either an aromatic or a branched aliphatic amino acid residue. 4 They affect a large number of biological activities 5 such as smooth muscle contraction and relaxation, immune system function, pain transmission, and neurogenic inflammation. They are also involved in various CNS disorders such as Parkinson’s, Huntington’s, and Alzheimer’s diseases, depression, anxiety, and psychosis. 6 These neurotransmitters are mainly represented by three major neuropeptides: substance P, (SP) and neurokinin A (NKA), originating from the same gene (TAC1), and neurokinin B (NKB) cleaved from the TAC3 gene. 7 These oligopeptides are the major endogenous ligands for the three human neurokinin recep- tor subtypes, termed NK 1 R, NK 2 R and NK 3 R, belonging to the large seven-transmembrane G protein-coupled receptor family. 4,8 While tachykinins are not specific for any individual NK receptor subtype, they do have differing affinities (NK 1 R: SP > NKA > NKB; NK 2 R: NKA > NKB > SP; NK 3 R: NKB > NKA > SP). NK 1 receptors (NK 1 R) are highly expressed in the CNS. 9a Biolog- ical and preclinical studies suggest that NK 1 R activation is closely related to depression and anxiety, and that NK 1 R blockade would therefore elicit both behavioral and physiological effects associated with antidepressant and anxiolytic activities. 9 Clinical trials in humans indicate that selective NK 1 receptor antagonists are effec- tive in treating chemotherapy-induced emesis (Aprepitant™, 1) (Fig. 1). 10 NK 3 receptors (NK 3 R) are almost exclusively found in the CNS (e.g., cortical regions, amygdala, hippocampus, mild-brain). 11 In vitro and in vivo studies suggest that NK 3 R activation results in the release of biogenic monoamines (i.e., dopamine, serotonine and noradrenaline). Consequently, it has been hypothesized that NK 3 R blockade with a selective antagonist could reduce the excit- atory activation of dopaminergic, serotonergic and noradrenergic systems and be associated with antipsychotic properties. 12 Thus, NK 3 R antagonism represents an alternative therapeutic approach for the treatment of schizophrenia. Recent data from clinical trials of Osanetant™ (2) 13 (Fig. 1) and Talnetant (3) 14 as selective NK 3 R antagonists in schizophrenia show significant improvement in positive symptoms (i.e., delu- sions, hallucinations, and behavioral disorders), with no major 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.12.033 ⇑ Corresponding author. E-mail address: stephen.hanessian@umontreal.ca (S. Hanessian).   Current address: Ra Pharmaceuticals, Inc., One Kendall Square, Suite B14301, Cambridge, MA 02139, United States. Bioorganic & Medicinal Chemistry Letters 24 (2014) 510–514 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl