The Kinetic Component in Drug Discovery: Using the Most Basic Pharmacological Concepts to Advance in Selecting Drugs to Combat CNS Diseases

Author(s): Rafael Franco*, Josema Castelló, Enric I. Canela.

Journal Name: Current Neuropharmacology

Volume 18 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

To reach the central nervous system (CNS), drugs must cross the brain-blood barrier and have appropriate pharmacokinetic/dynamic properties. However, in early drug discovery steps, the selection of lead compounds, for example, those targeting G-protein-coupled receptors (GPCRs), is made according to i) affinity, which is calculated in in vitro equilibrium conditions, and ii) potency, a signal transduction-related parameter, usually quantified at a fixed time-point in a heterologous expression system. This paper argues that kinetics must be considered in the early steps of lead compound selection. While affinity calculation requires the establishment of a ligand-receptor equilibrium, the signal transduction starts as soon as the receptor senses the agonist. Taking cAMP production as an example, the in vitro-measured cytoplasmic levels of this cyclic nucleotide do not depend on equilibrium dissociation constant, KD. Signaling occurs far from the equilibrium and correlates more with the binding rate (kon) than with KD. Furthermore, residence time, a parameter to consider in lead optimization, may significantly vary from in vitro to in vivo conditions. The results are discussed from the perspective of dopaminergic neurotransmission and dopaminereceptor- based drug discovery.

Keywords: Agonist binding, association, dissociation, equilibrium constant, GPCR, rate constants.

[1]
Hornykiewicz, O. The discovery of dopamine deficiency in the parkinsonian brain. J. Neural Transm. Suppl., 2006, 70(70), 9-15.
[http://dx.doi.org/10.1007/978-3-211-45295-0_3] [PMID: 17017502]
[2]
Olanow, C.W.; Agid, Y.; Mizuno, Y.; Albanese, A.; Bonuccelli, U.; Damier, P.; De Yebenes, J.; Gershanik, O.; Guttman, M.; Grandas, F.; Hallett, M.; Hornykiewicz, O.; Jenner, P.; Katzenschlager, R.; Langston, W.J.; LeWitt, P.; Melamed, E.; Mena, M.A.; Michel, P.P.; Mytilineou, C.; Obeso, J.A.; Poewe, W.; Quinn, N.; Raisman-Vozari, R.; Rajput, A.H.; Rascol, O.; Sampaio, C.; Stocchi, F. Levodopa in the treatment of Parkinson’s disease: current controversies. Mov. Disord., 2004, 19(9), 997-1005.
[http://dx.doi.org/10.1002/mds.20243] [PMID: 15372588]
[3]
Birkmayer, W.; Hornykiewicz, O. The L-dihydroxyphenylalanine (L-DOPA) effect in Parkinson’s syndrome in man: On the pathogenesis and treatment of Parkinson akinesis. Arch. Psychiatr. Nervenkr. Z. Gesamte Neurol. Psychiatr., 1962, 203, 560-574.
[http://dx.doi.org/10.1007/BF00343235] [PMID: 13971142]
[4]
Birkmayer, W.; Hornykiewicz, O. Additional experimental studies on L-DOPA in Parkinson’s syndrome and reserpine parkinsonism. Arch. Psychiatr. Nervenkr., 1964, 206, 367-381.
[http://dx.doi.org/10.1007/BF00341704] [PMID: 14345318]
[5]
Moore, R.Y. Principles of synaptic transmission. Ann. N. Y. Acad. Sci., 1993, 695, 1-9.
[http://dx.doi.org/10.1111/j.1749-6632.1993.tb23018.x] [PMID: 7902053]
[6]
Meder, D. The role of dopamine in the brain - lessons learned from Parkinson’s disease. Neuroimage, 2019, 15(190), 79-93.
[http://dx.doi.org/10.1016/j.neuroimage.2018.11.021] [PMID: 30465864]
[7]
Owesson-White, C.; Belle, A.M.; Herr, N.R.; Peele, J.L.; Gowrishankar, P.; Carelli, R.M.; Wightman, R.M. Cue-evoked Dopamine release rapidly modulates D2 neurons in the nucleus accumbens during motivated behavior. J. Neurosci., 2016, 36(22), 6011-6021.
[http://dx.doi.org/10.1523/JNEUROSCI.0393-16.2016] [PMID: 27251622]
[8]
Kara, E.; Lin, H.; Strange, P.G. Co-operativity in agonist binding at the D2 dopamine receptor: evidence from agonist dissociation kinetics. J. Neurochem., 2010, 112(6), 1442-1453.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06554.x] [PMID: 20050980]
[9]
Frank, A.; Kiss, D.J.; Keserű, G.M.; Stark, H. Binding kinetics of cariprazine and aripiprazole at the dopamine D3 receptor. Sci. Rep., 2018, 8(1), 12509.
[http://dx.doi.org/10.1038/s41598-018-30794-y] [PMID: 30131592]
[10]
Silvano, E.; Millan, M.J.; Mannoury la Cour, C.; Han, Y.; Duan, L.; Griffin, S.A.; Luedtke, R.R.; Aloisi, G.; Rossi, M.; Zazzeroni, F.; Javitch, J.A.; Maggio, R. The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors. Mol. Pharmacol., 2010, 78(5), 925-934.
[http://dx.doi.org/10.1124/mol.110.065755] [PMID: 20702763]
[11]
Tonge, P.J. Drug-Target Kinetics in Drug Discovery. ACS Chem. Neurosci., 2018, 9(1), 29-39.
[http://dx.doi.org/10.1021/acschemneuro.7b00185] [PMID: 28640596]
[12]
Filmore, D. 2004, It’s a GPCR world. Mod. drug Discov., 7, 24-27.
[13]
Jacoby, E.; Bouhelal, R.; Gerspacher, M.; Seuwen, K. The 7 TM G-protein-coupled receptor target family. ChemMedChem, 2006, 1(8), 761-782.
[http://dx.doi.org/10.1002/cmdc.200600134] [PMID: 16902930]
[14]
Sriram, K.; Insel, P.A.G. Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol. Pharmacol., 2018, 93(4), 251-258.
[http://dx.doi.org/10.1124/mol.117.111062] [PMID: 29298813]
[15]
Martínez-Pinilla, E.; Rabal, O.; Reyes-Resina, I.; Zamarbide, M.; Navarro, G.; Sánchez-Arias, J.A.; de Miguel, I.; Lanciego, J.L.; Oyarzabal, J.; Franco, R. Two affinity sites of the cannabinoid subtype 2 receptor identified by a novel homogeneous binding Assay. J. Pharmacol. Exp. Ther., 2016, 358(3), 580-587.
[http://dx.doi.org/10.1124/jpet.116.234948] [PMID: 27358483]
[16]
Navarro, G.; Cordomí, A.; Casadó-Anguera, V.; Moreno, E.; Cai, N.S.; Cortés, A.; Canela, E.I.; Dessauer, C.W.; Casadó, V.; Pardo, L.; Lluís, C.; Ferré, S. Evidence for functional pre-coupled complexes of receptor heteromers and adenylyl cyclase. Nat. Commun., 2018, 9(1), 1242.
[http://dx.doi.org/10.1038/s41467-018-03522-3] [PMID: 29593213]
[17]
Bondar, A.; Lazar, J. The G protein Gi1 exhibits basal coupling but not preassembly with G protein-coupled receptors. J. Biol. Chem., 2017, 292(23), 9690-9698.
[http://dx.doi.org/10.1074/jbc.M116.768127] [PMID: 28438833]
[18]
Weis, W.I.; Kobilka, B.K. The molecular basis of G protein-coupled receptor activation. Annu. Rev. Biochem., 2018, 87, 897-919.
[http://dx.doi.org/10.1146/annurev-biochem-060614-033910] [PMID: 29925258]
[19]
Muñoz, P. Dopamine oxidation and autophagy. Parkinsons Dis., 2012, 2012, 1-13.
[20]
Beaulieu, J-M.; Espinoza, S.; Gainetdinov, R.R. Dopamine receptors - IUPHAR Review 13. Br. J. Pharmacol., 2015, 172(1), 1-23.
[http://dx.doi.org/10.1111/bph.12906] [PMID: 25671228]
[21]
Tiberi, M.; Caron, M.G. High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype. J. Biol. Chem., 1994, 269(45), 27925-27931.
[PMID: 7525564]
[22]
Freedman, S.B.; Patel, S.; Marwood, R.; Emms, F.; Seabrook, G.R.; Knowles, M.R.; McAllister, G. Expression and pharmacological characterization of the human D3 dopamine receptor. J. Pharmacol. Exp. Ther., 1994, 268(1), 417-426.
[PMID: 8301582]
[23]
Copeland, R.A.; Pompliano, D.L.; Meek, T.D. Drug-target residence time and its implications for lead optimization. Nat. Rev. Drug Discov., 2006, 5(9), 730-739.
[http://dx.doi.org/10.1038/nrd2082] [PMID: 16888652]
[24]
Copeland, R.A. Drug-target residence time In: Thermodynamics and kinetics of drug binding; Keserü, G. M.; Swinney, D. C., Eds.; , 2015; pp. 157-167.
[http://dx.doi.org/10.1002/9783527673025.ch8]
[25]
Kozielska, M.; Johnson, M.; Pilla Reddy, V.; Vermeulen, A.; Li, C.; Grimwood, S.; de Greef, R.; Groothuis, G.M.; Danhof, M.; Proost, J.H. Pharmacokinetic-pharmacodynamic modeling of the D2 and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats. Pharm. Res., 2012, 29(7), 1932-1948.
[http://dx.doi.org/10.1007/s11095-012-0722-8] [PMID: 22437487]
[26]
de Witte, W.E.A.; Versfelt, J.W.; Kuzikov, M.; Rolland, S.; Georgi, V.; Gribbon, P.; Gul, S.; Huntjens, D.; van der Graaf, P.H.; Danhof, M.; Fernández-Montalván, A.; Witt, G.; de Lange, E.C.M. In vitro and in silico analysis of the effects of D2 receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations. Br. J. Pharmacol., 2018, 175(21), 4121-4136.
[http://dx.doi.org/10.1111/bph.14456] [PMID: 30051456]
[27]
Langlois, X.; Megens, A.; Lavreysen, H.; Atack, J.; Cik, M.; te Riele, P.; Peeters, L.; Wouters, R.; Vermeire, J.; Hendrickx, H.; Macdonald, G.; De Bruyn, M. Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia. J. Pharmacol. Exp. Ther., 2012, 342(1), 91-105.
[http://dx.doi.org/10.1124/jpet.111.190702] [PMID: 22490380]
[28]
Tresadern, G.; Bartolome, J.M.; Macdonald, G.J.; Langlois, X. Molecular properties affecting fast dissociation from the D2 receptor. Bioorg. Med. Chem., 2011, 19(7), 2231-2241.
[http://dx.doi.org/10.1016/j.bmc.2011.02.033] [PMID: 21421319]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 18
ISSUE: 3
Year: 2020
Page: [250 - 257]
Pages: 8
DOI: 10.2174/1570159X17666191001144309
Price: $65

Article Metrics

PDF: 16
HTML: 1