Why receptor reserve matters for neurokinin1 (NK1) receptor antagonists

Journal of Receptors and Signal Transduction

Volumn 33, Issue 6, 2013, Pages 333-337

  Trist, David G ^a   Ratti, Emiliangelo ^b   Bye, Alan ^c  

^a Analytical Pharmacologist   (Italy)

^b NeRRe Therapeutics Ltd   (United Kingdom)

^c Alan Bye and Company Limited   (United Kingdom)

Author keywords

Casopitant; Depression; Insomnia; Receptor occupancy; Vestipitant

Indexed keywords

CASOPITANT; NEUROKININ 1 RECEPTOR; PAROXETINE; RECEPTOR RESERVE; VESTIPITANT;

AROUSAL; BINDING AFFINITY; DRUG EFFICACY; FRONTAL CORTEX; HUMAN; INSOMNIA; LATENT PERIOD; MAJOR DEPRESSION; NEUROTRANSMISSION; PHASE 2 CLINICAL TRIAL (TOPIC); POLYSOMNOGRAPHY; RECEPTOR OCCUPANCY; REVIEW; SCORING SYSTEM; SLEEP TIME;

ANTIDEPRESSIVE AGENTS; DEPRESSIVE DISORDER, MAJOR; FLUOROBENZENES; HUMANS; NEUROKININ-1 RECEPTOR ANTAGONISTS; PIPERAZINES; PIPERIDINES; RECEPTORS, NEUROKININ-1; SLEEP INITIATION AND MAINTENANCE DISORDERS; TISSUE DISTRIBUTION;

EID: 84890146724     PISSN: 10799893     EISSN: 15324281     Source Type: Journal    
DOI: 10.3109/10799893.2013.843194     Document Type: Review

References (30)

1. Stephenson RP. A modification of receptor theory. Br J Pharmacol 1956;11:379-3.
2. Black JW, Leff P. Operational models of pharmacological agonism. Proc R Soc Lond B 1983;220:141-62.
3. Furchgott RF. The use of b-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor-agonist complexes. In: Harper NJ, Simmonds AB, eds. Advances in drug research. London: Academic Press; 1966, 21-55.
4. Kenakin TP. Receptor reserve as a tissue misnomer. Trends Pharmacol Sci 1986;7:93-5.
5. Ebner K, Sartori SB, Singewald N. Tachykinin receptors as therapeutic targets in stress-related disorders. Curr Pharm Design 2009;15:1647-74.
6. Holmes A, Heilig M, Rupniak N, et al. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci 2003;24:580-8.
7. Brocco M, Dekeyne A, Mannoury la Cour C, et al. Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents. Eur Neuropsychopharmacol 2008;18:729-50.
8. Di Fabio R, Griffante C, Alvaro G, et al. Discovery process and pharmacological characterization of 2-(S)-(4-Fluoro- 2-methylphenyl)piperazine- 1-carboxylic Acid [1-(R)-(3,5-bis trifluoromethylphenyl)ethyl]methylamide (Vestipitant) as a potent, selective, and orally active NK1 receptor antagonist. J Med Chem 2009;52:3238-47.
9. Di Fabio R, Alvaro G, Griffante C, et al. Discovery and biological characterization of (2R,4S)-10-acetyl-N-{(1R)-1-[3,5- bis(trifluoromethyl) phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-Nmethyl- 4,40-bipiperidine-1- carboxamide as a new potent and selective neurokinin 1 (NK1) receptor antagonist clinical candidate. J Med Chem 2011;54:1071-9.
10. Ratti E, Bellew K, Bettica P, et al. Results from 2 randomized. double-blind, placebo-controlled studies of the novel nk1 receptor antagonist casopitant in patients with major depressive disorder. J Clin Psychopharmacol 2011;31:727-33.
11. Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998;28:1640-5.
12. Keller M, Montgomery S, Ball W, et al. Lack of efficacy of the substance P (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 2006;59: 216-23.
13. Kramer MS, Winokur A, Kelsey J, et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 2004; 29:385-92.
14. Chappell P. Effects of CP-122,721, a selective NK-1 receptor antagonist, in patients with MDD. Presented at NCDEU June 12, 2002 (referenced in McLean, S. Do substance P and the NK1 receptor have a role in depression and anxiety)? Curr Pharm Des 2005;11:1529-47
15. Ratti E, Bettica P, Alexander R, et al. Full central NK1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol 2013;27: 424-34.
16. GSK Clinical Study Register. 2003. NK20006 - an 8-week, randomized, double-blind, placebo-controlled, multicenter, fixeddose study comparing the efficacy and safety of a new chemical entity (NCE) or paroxetine to placebo in moderately to severely depressed patients with major depressive disorder. Available from: http://www.gsk-clinicalstudyregister.com/result-comp-list.jsp? compound=vestipitant [last accessed 30 Sep 2013].
17. Zamuner S, Rabiner EA, Fernandes SA, et al. A pharmacokinetic PET study of NK1 receptor occupancy. Eur J Nucl Med Mol Imaging 2012;39:226-35.
18. Carletti R, Griffante C, Pozzato C, et al. NK1 receptor occupancy and anxiolytic-like effect of the novel NK1 receptor antagonist Vestipitant (GW597599) in gerbil. Eur Neuropsychopharmacol 2005;15:S533-9.
19. GSK Clinical Study Register. 2009. NKI111364 - a 28-day, polysomnographic and subjective assessment of vestipitant (15 mg/ day) for the treatment of primary insomnia in adult outpatients. Available from: http://www.gsk- clinicalstudyregister.com/result-comp-list.jsp?compound=vestipitant [last accessed 30 Sep 2013].
20. GSK Clinical Study Register. 2006. GW679769/903 - a randomized, double-blind, placebo-controlled, cross-over study to evaluate the effects of GW679769 (30 mg and 90 mg) on sleep continuity, PSG sleep recordings, subjective sleep assessment, and daytime cognitive function in subjects with primary insomnia. Available from: http://www.gsk-clinicalstudyregister.com/result-comp- list.jsp?compound=casopitant [last accessed 30 Sep 2013].
21. Arai H, Emson PC. Regional distribution of neuropeptide K and other tachykinins (neurokinin A, neurokinin B and substance P) in rat central nervous system. Brain Res 1986;399:240-9.
22. Gobbi G, Blier P. Effect of neurokinin-1 receptor antagonists on serotoninergic, noradrenergic and hippocampal neurons: comparison with antidepressant drugs. Peptides 2005;26:1383-93.
23. Gobbi G, Cassano T, Radja F, et al. Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function. Eur Neuropsychopharmacol 2007;17:328-38.
24. Haddjeri N, Blier P. Sustained blockade of neurokinin-1 receptors enhances serotonin neurotransmission. Biol Psychiatry 2001;50: 191-9.
25. Gobert A, Brocco M, Dekeyne A, et al. Neurokinin-1 antagonists potentiate antidepressant properties of serotonin reuptake inhibitors, yet blunt their anxiogenic actions: a neurochemical, electrophysiological, and behavioral characterization. Neuropsychopharmacology 2009;34:1039-56.
26. Bondy B, Baghai TC, Minov C, et al. Substance P serum levels are increased in major depression: preliminary results. Biol Psychiatry 2003;53:538-42.
27. Geracioti Jr TD, Carpenter LL, Owens MJ, et al. Elevated cerebrospinal fluid substance P concentrations in posttraumatic stress disorder and major depression. Am J Psychiatry 2006;163: 637-43.
28. Yocca FD, Iben L, Meller E. Lack of apparent receptor reserve at postsynaptic 5-hydroxytryptamine 1A receptors negatively coupled to adenylyl cyclase activity in rat hippocampal membranes. Mol Pharmacol 1992;41:1066-72.
29. Ebner K, Singewald GM, Whittle N, et al. Neurokinin 1 receptor antagonism promotes active stress coping via enhanced septal 5-HT transmission. Neuropsychopharmacology 2008;33:1929-41.
30. Kalia M. Neurobiology of sleep. Metabol Clin Exp 2006;55:S2-6.