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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Design, Synthesis and Anxiolytic Activity Evaluation of N-Acyltryptophanyl- Containing Dipeptides, Potential TSPO Ligands#

Author(s): Tatiana A. Gudasheva*, Olga A. Deeva, Grigory V. Mokrov, Alina S. Dyabina, Milada A. Yarkova and Sergey B. Seredenin

Volume 15, Issue 4, 2019

Page: [383 - 399] Pages: 17

DOI: 10.2174/1573406415666181119164846

Price: $65

Abstract

Background: The 18 kDa translocator protein (TSPO), previously known as the peripheral- type benzodiazepine receptor, plays a key role for the synthesis of neurosteroids by promoting transport of cholesterol from the outer to the inner mitochondrial membrane, which is the ratelimiting step in neurosteroid biosynthesis. Neurosteroids interact with nonbenzodiazepine site of GABAa receptor causing an anxiolytic effect without the side effects.

Methods: Using the original peptide drug-based design strategy, the first putative dipeptide ligand of the TSPO N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23) was obtained. Molecular docking of GD-23 in the active pocket of the TSPO receptor using Glide software was carried out. The lead compounds GD-23 and its analogues were synthesized using activated succinimide esters coupling method. The anxiolytic activity of GD-23 and its analogues was investigated in vivo, using two validated behavioral tests, illuminated open field and elevated plus-maze.

Results: The in vivo studies revealed that the following parameters are necessary for the manifestation of anxiolytic activity of new compounds: the L-configuration of tryptophan, the presence of an amide group at the C-terminus, the specific size of the N-acyl substituent at the Nterminus. Compound GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide) demonstrated a high anxiolytic-like effect in the doses of 0.05–1.0 mg/kg i.p. comparable with that of diazepam. Compound GD-23 was also active in the open field test when was administered orally in the doses of 0.1-5.0 mg/kg. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by the antagonism of compound GD-23 with TSPO selective inhibitor PK11195 as well as with inhibitors of enzymes which are involved in the biosynthesis of neurosteroids, trilostane and finasteride.

Conclusion: A series of N-acyl-tryptophanyl-containing dipeptides were designed and synthesized as 18 kDa translocator protein (TSPO) ligands. Using a drug-based peptide design method a series of the first dipeptide TSPO ligands have been designed and synthesized and their anxiolytic activity has been evaluated. In general, some of the compounds displayed a high level of anxiolytic efficacy comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic activity of new compounds was proved using two methods. On this basis, the N-acyl-Ltryptophanyl- isoleucine amides could potentially be a novel class of TSPO ligands with anxiolytic activity.

Keywords: TSPO ligands, dipeptides, anxiolytic activity, elevated plus maze test, open field test, PK11195, trilostane, finasteride.

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[1]
Braestrup, C.; Squires, R.F. Specific benzodiazepine receptors in rat brain characterized by high-affinity 3H-diazepam binding. Proc. Natl. Acad. Sci. USA, 1977, 74, 3805-3809.
[2]
Papadopoulos, V.; Baraldi, M.; Guilarte, T.R.; Knudsen, T.B.; Lacapere, J-J.; Lindemann, P.; Norenberg, M.D.; Nutt, D.; Weizman, A.; Zhang, M.R.; Gavish, M. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol. Sci., 2006, 27, 402-409.
[3]
Scarf, A.M.; Ittner, L.M.; Kassiou, M. The translocator protein (18 kDa): central nervous system disease and drug design. J. Med. Chem., 2009, 52, 581-592.
[4]
Gavish, M.; Bachman, I.; Shoukrun, R.; Katz, Y.; Veenman, L.; Weisinger, G.; Weizman, A. Enigma of the peripheral benzodiazepine receptor. Pharmacol. Rev., 1999, 51, 629-650.
[5]
Anholt, R.R.; De Souza, E.B.; Oster-Granite, M.L.; Snyder, S.H. Peripheral- type benzodiazepine receptors: Autoradiographic localization in whole-body sections of neonatal rats. JPET, 1985, 233, 517-526.
[6]
Rupprecht, R.; Papadopoulos, V.; Rammes, G.; Baghai, T.C.; Fan, J.; Akula, N.; Groyer, G.; Adams, D.; Schumacher, M. Translocator protein (18kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat. Rev. Drug Discov., 2010, 9, 971-988.
[7]
Stocco, D.M.; Tu, L.N.; Zhao, A.H.; Selvaraj, V. PK11195 effect on steroidogenesis is not mediated through the translocator protein (TSPO). Endocrinology, 2014, 155(1), 6-9.
[8]
Verleye, M.; Akwa, Y.; Liere, P.; Ladurelle, N.; Pianos, A.; Eychenne, B.; Schumacher, M.; Gillardin, J.M. The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain. Pharmacol. Biochem. Behav., 2005, 82, 712-720.
[9]
Kozikowski, A.P.; Brewer, J.; Sun, S.; Costa, E.; Romeo, E.; Guidotti, A. Chemistry, binding affinities and behavioral properties of a new class of “antineophobic” mitochondrial DBI receptor complex (mDRC) ligands. J. Med. Chem., 1993, 36, 2908-2920.
[10]
Zhang, L-M.; Zhao, N.; Guo, W-Z.; Jin, Z-L.; Qiu, Z-K.; Chen, H-X.; Xue, R.; Zhang, Y-Z.; Yang, R-F.; Li, Y-F. Antidepressant-like and anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa). Neuropharmacology, 2014, 81, 116-125.
[11]
Mellon, S.H.; Gong, W.; Schonemann, M.D. Endogenous and synthetic neurosteroids in treatment of Niemann-Pick type C disease. Brain Res.Rev., 2008, 57, 410-420.
[12]
Li, H.; Degahardt, B.; Tobin, D.; Yao, Z-X.; Tasken, K.; Papadopoulos, V. Identification, localization and function in steroidogenesis of PAP7: A peripheral-type benzodiazepine receptor- and PKA (RIα)-associated protein. Mol. Endocrinol., 2001, 15, 2211-2228.
[13]
Michelle, L.J.; Selleri, S.; Kassiou, M. Development of ligands for the peripheral benzodiazepine receptor. Curr. Med. Chem., 2006, 13, 1991-2001.
[14]
Anzini, M.; Cappelli, A.; Vomero, S.; Seeber, M.; Menziani, M.C.; Langer, T.; Hagen, B.; Manzoni, C.; Bourguignon, J.J. Mapping and fitting the peripheral benzodiazepine receptor binding site by carboxamide derivatives. Comparison of different approaches to quantitative ligand-receptor interaction modeling. J. Med. Chem., 2001, 44, 1134-1150.
[15]
Taliani, S.; Pugliesi, I.; Da Settimo, F. Structural requirements to obtain highly potent and selective 18 kDa translocator protein (TSPO) ligands. Curr. Top. Med. Chem., 2011, 11, 860-886.
[16]
Nguyen, N.; Fakra, E.; Pradel, V.; Jouve, E.; Alquier, C.; Le Guern, M.E.; Micallef, J.; Blin, O. Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: A double-blind controlled study in general practice. Hum. Psychopharmacol. Clin. Exp., 2006, 21(3), 139-149.
[17]
Langer, S.Z.; Faure-Halley, C.; Seeburg, P.; Graham, D.; Arbilla, S. The selectivity of zolpidem and alpidem for the α1-subunit of the GABAA receptor. Euro. Neuropsychopharmacol., 1992, 2(3), 232-234.
[18]
Rupprecht, R.; Rammes, G.; Eser, D.; Baghai, T.C.; Schüle, C.; Nothdurfter, C.; Troxler, T.; Gentsch, C.; Kalkman, H.O.; Chaperon, F.; Uzunov, V.; McAllister, K.H.; Bertaina-Anglade, V.; La Rochelle, C.D.; Tuerck, D.; Floesser, A.; Kiese, B.; Schumacher, M.; Landgraf, R.; Holsboer, F.; Kucher, K. Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science, 2009, 24, 490-493.
[19]
Sanger, D.J.; Zivkovic, B. Discriminative stimulus effects of alpidem, a new imidazopyridine anxiolytic. Synthelabo Recherche, 1994, 113(3-4), 395-403.
[20]
Gudasheva, T.A. Theoretical grounds and technologies for dipeptide drug development. Russian. Chem. Bull., 2015, 64(9), 2012-2021.
[21]
Gudasheva, T.A.; Voronina, T.A.; Ostrovskaya, R.U.; Zaitseva, N.I.; Bondarenko, N.A.; Briling, V.K.; Asmakova, L.S.; Rozantsev, G.G.; Seredenin, S.B. Design of N-acylprolyltyrosine “tripeptoid” analogues of neurotensin as potential atypical antipsychotic agents. J. Med. Chem., 1998, 41, 284-290.
[22]
Gudasheva, T.A.; Voronina, T.A.; Ostrovskaya, R.U.; Rozantsev, G.G.; Vasilevich, N.I.; Trofimov, S.S.; Kravchenko, E.V.; Skoldinov, A.P.; Seredenin, S.B. Synthesis and antiamnesic activity of a series of IV-acylprolyl-containing dipeptides. Eur. J. Med. Chem., 1996, 31, 151-157.
[23]
Seredenin, S.B.; Voronina, T.A.; Gudasheva, T.A.; Ostrovskaya, R.U.; Rozantsev, G.G.; Skoldinov, A.P.; Trofimov, S.S.; Halikas, J.; Garibova, T.L. Biologically active N-acylprolyldipeptides having antiamnestic, antihypoxic effects. Patent No. 5.439.930 USA 1995.
[24]
Kovalenok, T.V.; Shabanova, A.A.; Bogdanova, I.O.; Sunyakov, T.S.; Ivashkina, N.Y.; Bogdan, N.G.; Neznamov, G.G. Influence of the original antipsychotic drug Dilept on cognitive functions in patient with schizotypal disorder. Eksp. Klin. Farmakol., 2017, 80(8), 8-14.
[25]
Anzini, M. Molecular basis of peripheral vs central benzodiazepine receptor selectivity in a new class of peripheral benzodiazepine receptor ligands related to alpidem. J. Med. Chem., 1996, 39, 4275-4284.
[26]
Gudasheva, T.A.; Deeva, O.A.; Mokrov, G.V.; Yarkov, S.A.; Yarkova, M.A.; Seredenin, S.B. The first dipeptide ligand of translocator protein: design and anxiolytic activity. Doklady. Biochem. Biophys., 2015, 464, 290-293.
[27]
Lobell, M.; Schneider, M.P. Pronase catalyzed peptide syntheses. J. Chem. Soc. Perkin Trans., 1998, 319-326.
[28]
Jaremko, L.; Jaremko, M.; Giller, K.; Becker, S.; Zweckstetter, M. Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science, 2014, 343, 1363-1366.
[29]
Bernstein, F.C.; Koetzle, T.F.; Williams, G.J.B.; Meyer, E.F.J.; Brice, M.D.; Rodgers, J.R.; Kennard, O.; Shimanouchi, T.; Tasumi, M. The Protein Data Bank: A computer-based archival file for macromolecular structures. J. Mol. Biol., 1977, 112, 535-542.
[30]
Schrodinger, Release 2015-4: Maestro, version 10.4; Schrödinger, LLC: New York, NY, 2015.
[31]
Schrodinger, Release. 2015-2: LigPrep; Schrödinger, LLC: New York, NY, 2015.
[32]
Celik, I.; Abdel-Fattah-Ashraf, A.A. Convenient synthesis of C-terminal di- and tri-peptide amides from N-protected dipeptidoylbenzotriazoles. Tetrahedron, 2009, 65, 4923-4929.
[33]
Wieland, T.; Freter, K.; Gross, E. Über die Giftstoffe des grünen Knollenblätterpilzes, XVII Versuche zur Synthese Phalloin-ähnlicher Cyclopeptide. Justus Liebigs Ann. Chem., 1959, 626, 154-173.
[34]
Anderson, G.W.; Zimmerman, J.E.; Callahan, F.M. The use of esters of N-hydroxysuccinimide in peptide synthesis. J. Am. Chem. Soc., 1964, 86, 1839-1842.
[35]
Povarnina, P.Y.; Yarkov, S.A.; Gudasheva, T.A.; Yarkova, M.A.; Seredenin, S.B. The novel dipeptide translocator protein ligand, referred to as GD-23, exerts anxiolytic and nootropic activities. Acta Naturae., 2015, 7, 108-112.
[36]
Seredenin, S.B.; Vedernikov, A.A. Effect of psychotropic drugs on behavior of inbred mice under emotional stress. Bull. Exp. Biol. Med., 1979, 88(1), 714-716.
[37]
Bruhwyler, J.; Chleide, E.; Liegeois, J.F.; Delarge, J.; Mercier, M. Anxiolytic potential of sulpiride, clozapine and derivatives in the open-field test. Pharma. Biochem. Behav., 1990, 36, 57-61.
[38]
Seredenin, S.B.; Longo, V.; Gaviraghi, G. Biological basis of individual sensitivity to psychotropic drugs; Seredenin, S.B., Ed.; Edinburgh Graffham Press: London, 1994, p. 304.
[39]
File, S.E. Factors controlling measures of anxiety and responses to novelty in the mouse. Behav. Brain Res., 2001, 125, 151-157.
[40]
Cole, J.C.; Rodgers, R.J. Ethological comparison of the effects of diazepam and acute/chronic imipramine on the behaviour of mice in the elevated plus-maze. Pharmacol. Biochem. Behav., 1995, 52, 473-478.
[41]
Kita, A.; Kohayakawa, H.; Kinoshita, T.; Ochi, Y.; Nakamichi, K.; Kurumiya, S.; Furukawa, K.; Oka, M. Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand. Br. J. Pharmacol., 2004, 142, 1059-1072.
[42]
Le Fur, G.; Guilloux, F.; Rufat, P.; Benavides, J.; Uzan, A.; Renault, C.; Dubroeucq, M.C.; Guérémy, C. Peripheral benzodiazepine binding sites: Effect of PK 11195, 1-(2-chlorophenyl)-n-methyl-(1-methylpropyl)-3 isoquinolinecarboxamide: II. In vivo studies. Life Sci., 1983, 32, 1849-1856.
[43]
Martinez, J.A.; Fargeas, M.J.; Bueno, L. Physical dependence on diazepam: Precipitation of abstinence syndromes by peripheral and central benzodiazepine receptor antagonists. Pharmacol. Biochem. Behav., 1992, 41, 461-464.
[44]
Potts, G.O.; Creange, J.E.; Hardomg, H.R.; Schane, H.P. Trilostane, an orally active inhibitor of steroid biosynthesis. Steroids, 1978, 32, 257-267.
[45]
Rittmaster, R.S.; Antonian, L.; New, M.I.; Stoner, E. Effect of finasteride on adrenal steroidogenesis in men. J. Androl., 1994, 15, 298-301.
[46]
Kita, A.; Furukawa, K. Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice. Pharmacol. Biochem. Behav., 2008, 89, 171-178.
[47]
Schrödinger , Release. 2015-4: Schrödinger Suite 2015-4 Protein Preparation Wizard; Epik version 3.4, Schrödinger, LLC, New York, NY, 2015; Impact version 6.9, Schrödinger, LLC, New York, NY, 2015; Prime version 4.2; Schrödinger, LLC: New York, NY, 2015.
[48]
Schechter, B.; Schechter, I.; Sela, M. Antibody combining sites to a series of peptide determinants of increasing size and defined structure. J. Biol. Chem., 1970, 245, 1438-1439.
[49]
Hoekstra, W.J.; Sunder, S.S.; Cregge, R.J.; Ashton, L.A.; Stewart, K.T.; King, C-H.R. Large-scale synthesis of anticoagulant decapeptide MDL 28050. Tetrahedron, 1992, 48, 307-318.
[50]
Goodman, C.A.; Hamaker, C.G.; Hitchcock, S.R. Synthesis and evaluation of some variants of the Nefkens’ reagent. Tetrahedron Lett., 2013, 54, 6012-6014.
[51]
Thorsen, M.; Yde, B.; Pedersen, U.; Clauden, K.; Lawesson, S.O. Studies on amino acids and peptides-V: synthesis of endothionated melanostatin analogs. Tetrahedron, 1983, 39, 3429-3436.
[52]
Toumi, M.; Couty, F.; Evano, G. Total synthesis of the cyclopeptide alkaloid paliurine E. Insights into macrocyclization by ene-enamide RCM. J. Org. Chem., 2008, 4, 1270-1281.
[53]
Ressler, C.; De Vigneaut, V. The isoglutamine isomer of oxytocin: its synthesis and comparison with oxytocin. J. Am. Chem. Soc., 1957, 79, 4511-4515.

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