Biased signalling and allosteric machines: New vistas and challenges for drug discovery

British Journal of Pharmacology

Volumn 165, Issue 6, 2012, Pages 1659-1669

  Kenakin, Terry P ^a  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

drug classification; drug nomenclature; receptor agonists and antagonists

Indexed keywords

3 AMINO 5 CHLORO 6 METHOXY 4 METHYL THIENO (2,3 B) PYRIDINE 2 CARBOXYLIC ACID CYCLOPROPYLAMIDE; 4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; 5 CHLORO 3 ETHYL 1H INDOLE 2 CARBOXYLIC ACID [2 (4 PIPERIDIN 1 YL PHENYL)ETHYL]AMIDE; 6,7 DICHLORO 2 METHYLSULFONYL 3 TERT BUTYLAMINOQUINOXALINE; APLAVIROC; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; CYCLIC AMP; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 [7-36] AMIDE; IFENPRODIL; LY 2033298; MEMBRANE PROTEIN; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; NOVO2; ORG 27569; RANTES; SEVEN TRANSMEMBRANE RECEPTOR; UNCLASSIFIED DRUG;

ALLOSTERISM; BINDING AFFINITY; COMPLEX FORMATION; DRUG ANTAGONISM; DRUG EFFICACY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; LIGAND BINDING; OLIGOMERIZATION; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; RECEPTOR BINDING; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; BINDING SITES; DRUG DISCOVERY; HUMANS; LIGANDS; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84857497773     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2011.01749.x     Document Type: Review

References (52)

1. Angers S, Salahpour A, Bouvier M, (2002). Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. Annu Rev Pharmacol Toxicol 42: 409-435.
2. Black JW, Leff P, (1983). Operational models of pharmacological agonist. Proc R Soc Lond B Biol Sci 220: 141-162.
3. Bouvier M, (2001). Oligomerization of G-protein coupled transmitter receptors. Nat Rev Neurosci 2: 274-286.
4. Breitwieser G, (2004). G protein-coupled receptor oligomerization: implications for G protein activation and cell signaling. Circ Res 9/23: 17-27.
5. Christopoulos A, Kenakin TP, (2002). G-protein coupled receptor allosterism and complexing. Pharmacol Rev 54: 323-374.
6. Ehlert FJ, (1988). Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. Mol Pharmacol 33: 187-194.
7. Ehlert FJ, (2005). Analysis of allosterism in functional assays. J Pharmacol Exp Ther 315: 740-754.
8. Ellis J, Huyler J, Brann MR, (1991). Allosteric regulation of cloned M1-M5 muscarinic receptor subtypes. Biochem Pharmacol 42: 1927-1932.
9. Franco R, Casadõ V, Cortés A, Mallol J, Ciruela F, Ferré S, et al,. (2008). G-protein-coupled receptor heteromers: function and ligand pharmacology. Br J Pharmacol 153: S90-S98.
10. Giraldo J, (2008). On the fitting of binding data when receptor dimerization is suspected. Br J Pharmacol 155: 17-23.
11. Gnagey AL, Seidenberg M, Ellis J, (1999). Site-directed mutagenesis reveals two epitopes involved I nthe subtype selectivity of the allosteric interactions of gallamine at muscarinic acetylcholine receptors. Mol Pharmacol 56: 1245-1253.
12. Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, et al,. (2005). The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307: 14334-11440.
13. Gurevich VV, Gurevich EV, (2008). How and why do GPCRs dimerize. Trends Pharmacol Sci 29: 234-240.
14. Gurwitz D, Haring R, (2003). Ligand selective signaling and high content screening for GPCR drugs. Drug Discov Today 8: 1108-1109.
15. Hay DL, Poyner DR, Sexton PM, (2006). GPCR modulation by RAMPS. Pharmacol Ther 109: 173-197.
16. Hermans E, (2003). Biochemical and pharmacological control of the multiplicity of coupling at G-protein coupled receptors. Pharmacol Ther 99: 25-44.
17. James JR, Oliveira MI, Carmo AM, Iaboni A, Davis SJ, (2006). A rigorous experimental framework for detecting protein oligomerization using bioluminescence resonance energy transfer. Nat Methods 3: 1001-1006.
18. Johnson MP, Nisenbaum ES, Large TH, Emkey R, Baez M, Kingston AE, (2004). Allosteric modulators of metabotropic glutamate receptors: leassons learnt from mGlu1, mGlu2, and mGlu5 potentiators and agonists. Biochem Soc Trans 32: 881-887.
19. Kenakin TP, (1995). Agonist-receptor efficacy II: agonist-trafficking of receptor signals. Trends Pharmacol Sci 16: 232-238.
20. Kenakin TP, (2003). Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol Sci 24: 346-354.
21. Kenakin TP, (2005). New concepts in drug discovery: collateral efficacy and permissive antagonism. Nat Rev Drug Discov 4: 919-927.
22. Kenakin TP, (2007). Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol Sci 28: 407-415.
23. Kenakin TP, (2011). Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther 336: 296-302.
24. Kenakin TP, Miller LJ, (2010). Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev 62: 265-304.
25. Kew JNC, Trube G, Kemp JA, (1996). A novel mechanism of activity-dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurons. J Physiol 497 (3): 761-772.
26. Koole C, Wooten D, Simms J, Valant C, Sridhar R, Woodman OL, et al,. (2010). Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pthway-selective manner: implications for drug screening. Mol Pharmacol 78: 456-465.
27. Krause RM, Buisson B, Bertrand S, Corringer P-J, Galzi J-L, Changeux J-P, et al,. (1998). A positive allosteric effector of the a7 neuronal nicotinic acetylcholine receptor. Mol Pharmacol 53: 283-294.
28. Kuhmann SE, Pugach P, Kunstman KJ, Taylor J, Stanfield RL, Snyder A, et al,. (2004). Genetic and phenotypic analyses of human immunodeficiency virus type 1 escape form small-molecule CCR inhibitor. J Virol 78: 2790-2807.
29. Leach K, Sexton PM, Christopoulos A, (2007). Allosteric GPCR modulators: taking advantage of permissive pharmacology. Trends Pharmacol Sci 28: 382-390.
30. Leach K, Sexton PM, Christopoulos A, (2011). Quantification of Allosteric Interactions at G Protein-Coupled Receptors Using Radioligand Binding Assays.
31. Liang JS, Carsi-Gabrenas J, Krajesewski JL, McCafferty JM, Parkerson SL, Santiago MP, et al,. (1996). Anti-muscarinic toxins from dendroaspis angusticeps. Toxicon 34: 1257-1267.
32. Litschig S, Gasparini F, Ruegg DF, Stoehr N, Flor PJ, Vranesic I, et al,. (1999). CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol Pharmacol 55: 453-461.
33. Maeda K, Nakata H, Koh Y, Miyakawa T, Ogata H, Takaoka Y, et al,. (2004). Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J Virol 78: 8654-8662.
34. Maelicke A, Albuquerque EX, (1996). New approach to drug therapy of Alzheimer's dementia. Drug Discov Today 1: 53-59.
35. Mailman RB, (2007). GPCR functional selectivity has therapeutic impact. Trends Pharmacol Sci 29: 390-396.
36. Melchiorre C, Minarini A, Angeli P, Giardina D, Gulini U, Quaglia W, (1989). Polymethylene tetraamines as muscarinic receptor probes. Trends Pharmacol Sci 10 (Suppl.): 55-59.
37. Milligan G, (2008). A day in the life of a G protein coupled receptor: the contribution to function of G protein-coupled receptor dimerization. Br J Pharmacol 153: S216-S229.
38. Milligan G, Canals M, Pediani JD, Ellis J, Lopez-Gimenez JF, (2006). The Role of GPCR dimerisation/oligomerisation in receptor signalling. Ernst Schering Found Symp Proc 48: 145-161.
39. Muniz-Medina VM, Jones S, Maglich JM, Galardi C, Hollingsworth RE, Kazmierski WM, et al,. (2009). The relative activity of 'function sparing' HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property? Mol Pharmacol 75: 490-501.
40. Onaran HO, Costa T, (1997). Agonist efficacy and allosteric models of receptor action. Ann NY Acad Sci 812: 98-115.
41. Onaran HO, Scheer A, Cotecchia S, Costa T, (2002). A look at receptor efficacy. From the signaling network of the cell to the intramolecular motion of the receptor. In:, Kenakin TP, Angus JA, (eds). The Pharmacology of Functional, Biochemical, and Recombinant Systems Handbook of Experimental Pharmacology, Vol. 148. Springer: Heidelberg, pp. 217-280.
42. Perez DM, Karnick SS, (2005). Multiple signaling states of G-protein coupled receptors. Pharmacol Rev 57: 147-161.
43. Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, et al,. (2005). Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol 68: 1484-1495.
44. Samama P, Cotecchia S, Costa T, Lefkowitz RJ, (1993). A mutation-induced activated state of the b2-adrenergic receptor: extending the ternary complex model. J Biol Chem 268: 4625-4636.
45. Suratman S, Leach K, Sexton PM, Felder CC, Loiacono RE, Christopoulos A, (2011). Impact of species variability and 'probe-dependence' on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor. Br J Pharmacol 162: 1659-1670.
46. Trankle C, Weyand A, Schroter A, Mohr K, (1999). Using a radioalloster to test predictions of the cooperativity model for gallamine binding to the allosteric site of muscarinic acetylcholine (m2) receptors. Mol Pharmacol 56: 962-965.
47. Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, et al,. (2002). HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci U S A 99: 395-400.
48. Umbarger HE, (1956). Evidence for a negative feedback mechanism in the biosynthesis of isoleucine. Science 123: 848.
49. Watson C, Jenkinson S, Kazmierski W, Kenakin TP, (2005). The CCR5 Receptor-based mechanism of action of 873140, a potent allosteric non-competitive HIV entry-inhibitor. Mol Pharmacol 67: 1268-1282.
50. Weiss JM, Morgan PH, Lutz MW, Kenakin TP, (1996a). The cubic ternary complex receptor-occupancy model. I. Model description. J Theor Biol 178: 151-167.
51. Weiss JM, Morgan PH, Lutz MW, Kenakin TP, (1996b). The cubic ternary complex receptor-occupancy model. II. Understanding apparent affinity. J Theor Biol 178: 169-182.
52. Weiss JM, Morgan PH, Lutz MW, Kenakin TP, (1996c). The cubic ternary complex receptor-occupancy model. III. Resurrecting efficacy. J Theor Biol 181: 381-397.