Predicting therapeutic value in the lead optimization phase of drug discovery

Nature Reviews Drug Discovery

Volumn 2, Issue 6, 2003, Pages 429-438

  Kenakin, Terry ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (3 TERT BUTYLAMINO 2 HYDROXYPROPOXY) 2 BENZIMIDAZOLONE; ADENOSINE RECEPTOR STIMULATING AGENT; ALPHA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; ALPHA ADRENERGIC RECEPTOR STIMULATING AGENT; BETA 1 ADRENERGIC RECEPTOR BLOCKING AGENT; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; BETA 3 ADRENERGIC RECEPTOR BLOCKING AGENT; BRADYKININ RECEPTOR AGONIST; CANNABINOID RECEPTOR AGONIST; CHOLECYSTOKININ RECEPTOR BLOCKING AGENT; DOPAMINE 2 RECEPTOR STIMULATING AGENT; G PROTEIN COUPLED RECEPTOR; MUSCARINIC AGENT; OPIATE AGONIST; PHENTOLAMINE; SEROTONIN 1A ANTAGONIST; SEROTONIN 2A AGONIST; SEROTONIN 2C AGONIST; TACHYKININ RECEPTOR AGONIST; CELL SURFACE RECEPTOR; DRUG; GUANINE NUCLEOTIDE BINDING PROTEIN; RECOMBINANT PROTEIN;

CONCENTRATION RESPONSE; DNA RECOMBINATION; DRUG ACTIVITY; DRUG DETERMINATION; DRUG DEVELOPMENT; DRUG EFFECT; DRUG EFFICACY; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG SCREENING; DRUG SELECTIVITY; GENETIC ANALYSIS; GENOTYPE PHENOTYPE CORRELATION; HUMAN; NONHUMAN; PHARMACOGENOMICS; PRIORITY JOURNAL; PROCESS OPTIMIZATION; REVIEW; STIMULUS RESPONSE; ANIMAL; FORECASTING; GENETICS; METABOLISM; METHODOLOGY; PHARMACEUTICS;

ANIMALS; FORECASTING; GTP-BINDING PROTEINS; HUMANS; PHARMACEUTICAL PREPARATIONS; RECEPTORS, CELL SURFACE; RECOMBINANT PROTEINS; TECHNOLOGY, PHARMACEUTICAL;

EID: 0037794320     PISSN: 14741776     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrd1110     Document Type: Review

References (100)

1. Marchese, A., George, S. R., Kolakowski, L. F., Lynch, K. R. & O'Dowd, B. F. Novel GPCRs and their endogenous ligands: expanding the boundaries of physiology and pharmacology. Trends Pharmacol. Sci. 20, 370-375 (1999).
2. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304-1351 (2001).
3. Drews, J. Drug discovery: a historical perspective. Science. 287, 1960-1964(2000).
4. Black, J. W. & Leff, P. Operational models of pharmacological agonist. Proc. R. Soc. Lond., B, Biol. Sci., 220, 141-162 (1983).
5. Kenakin, T. P. Efficacy at G-protein coupled receptors. Ann. Rev. Pharmacol. Toxicol. 42, 349-379 (2002).
6. Kost, T. A. & Condreay, J. P. Recombinant baculoviruses as mammalian cell gene-delivery vectors. Trends Biotech. 20, 173-180 (2002).
7. Brady, A. E. & Limbird, L. E. G-protein-coupled receptor interacting proteins: emerging roles in localization and signal transduction. Cell. Signal. 14, 297-309 (2002).
8. Horne, W. C., Shyu, J.-F, Chakraborty, M. & Baron, R. Signal transduction by calcitonin: multiple ligands, receptors, and signaling pathways. Trends Endocrinol. Metab. 5, 395-401(1994).
9. Laugwitz K. -L. et al. The human thyrotropin receptor: A heptahelical receptor capable of stimulating members of all four G protein families. Proc. Natl Acad. Sci. USA 93, 116-1120 (1996).
10. Kenakin, T. P. Differences between natural and recombinant G-protein coupled receptor systems with varying receptor/G-protein stoichiometry. Trends Pharmacol. Sci. 18, 456-464 (1997).
11. Cordeaux, Y. et al. Influence of receptor number on functional responses elicited by agonists acting at the human adenosine A1 receptor: Evidence for signaling pathway-dependent changes in agonist potency and relative intrinsic activity. Mol. Pharmacol. 58, 1075-1084 (2000).
12. 2C receptors revealed by antibody capture assays: Influence of receptor reserve and relationship to agonist-directed trafficking. Mol. Pharmacol. 62, 578-589 (2002).
13. 2-adrenoceptors. Biochem. Pharmacol. 62, 913-922(2002).
14. Costa, T., Klinz, F. -J., Vachon, L. & Herz, A. Drug efficacy at guanine nucleotide-binding regulatory protein-linked receptors: Thermodynamic interpretation of negative antagonism and of receptor activity in the absence of ligand. Mol. Pharmacol. 40, 744-754 (1988).
15. Arey B. J. et al. Induction of promiscuous G-protein-coupling of the follicle-stimulating hormone (FSH) receptor: A novel mechanism for transducing pleiotropic actions of FSH isoforms. Mol. Endocrinol. 11, 517-526 (1997).
16. Kenakin, T. P. Agonist-receptor efficacy II: Agonist-trafficking of receptor signals. Trends Pharmacol. Sci. 16, 232-238 (1995).
17. Kenakin, T. P. Inverse, protean, and ligand-selective agonism: Matters of receptor conformation. FASEB J. 15, 598-611 (2001).
18. Kenakin, T. P. Efficacy at G-protein-coupled receptors. Nature Rev. Drug Discov. 1, 103-109 (2002).
19. Spengler, D. et al. Differential signal transduction by five splice variants of the PACAP receptor. Nature 365, 170-175 (1993).
20. Meller, E., Puza, T., Diamond, J., Lieu, H.-D. & Bohmaker, K. Comparative effects of receptor inactivation, 17β-estradiol and pertussis toxin on dopaminergic inhibition of prolactin-secretion in vitro. J. Pharmacol. Exp. Ther. 263, 462-469(1992).
21. Robb, S. et al. Agonist-specific coupling of a cloned Drosophila octopamine/tyramine receptor to multiple second messenger systems. EMBO J. 13, 1325-1332 (1994).
22. Sagan, S., Karoyan, P., Chassaing, G. & Lavielle, S. Further delineation of the two binding sites (R*n) associated with tachykinin neurokinin-1 receptors using [3-prolinomethionine ]SP analogues. J. Biol. Chem. 274, 23770-23776(1999).
23. 2-adrenoceptor coupling to Gs-, Gi-, and Gq- proteins. Mol. Pharmacol. 58, 954-966 (2000).
24. s complex: evidence for agonist-specific states. Mol. Pharmacol. 52, 144-154 (1997).
25. s interactions: evidence for multiple receptor conformations. Mol. Pharmacol. 56, 348-358 (1999).
26. Chidiac, P., Hebert, T. E., Valiquette, M., Dennis, M. & Bouvier, M. Inverse agonist activity of β-adrenergic antagonists. Mol. Pharmacol. 45, 490-9 (1994).
27. 2-adrenergic, receptor. Mol. Pharmacol. 50, 662-666 (1996).
28. Gether, J. et al. Structural instability of a constitutively active G-protein coupled receptor. J. Biol. Chem. 272, 2587-2590 (1997).
29. i/1o activation profiles in CHO cells expressing human muscarinic acetylcholine receptors: Dependence on agonist as well as receptor-subtype. Br. J. Pharmacol. 132, 950-958(2001).
30. Watson, C. A. et al. The use of stimulus-biased assay systems to detect agonist-specific receptor active-states: implications for the trafficking of receptor stimulus by agonists. Mol. Pharmacol. 58, 1230-1238 (2000).
31. 2A-adrenoceptor responses in HEL 92.1.7 cells. Br. J. Pharmacol. 132, 1477-1484(2001).
32. 2A- adrenoceptors. Mol. Pharmacol. 53, 963-968 (1998).
33. MacKinnon, A. C., Waters, C., Jodrell, D., Haslett, C. & Sethi, T. Bombesin and substance P analogues differentially regulate G-protein coupling to the bombesin receptor. J. Biol. Chem. 276, 28083-28091(2001).
34. Takasu, H., Gardella, T. J., Luck, M. D., Potts, J. T. & Bringhurst, F. R. Amino-terminal modifications of human parathyroid hormone (PTH) selectively alter phospholipase C signaling via type 1 PTH receptor: Implications for design of signal-specific PTH ligands. Biochem. 38, 13453-13460 (1999).
35. 2A receptors are labeled by agonists and discriminated by antagonists. Mol. Pharmacol. 60, 690-699 (2001).
36. Berg, K. A. et al. Effect pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol. Pharmacol. 54, 94-104 (1998).
37. Bonhaus, D. W., Chang, L. K., Kwan, J. & Martin, G. R. Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular process. J. Pharmacol. Exp. Ther. 287, 884-888 (1998).
38. 2 receptors. Mol. Pharmacol. 56, 1362-1369 (1999).
39. 2 bradykinin receptor activity determines the action of partial agonists as agonists or inverse agonists. J. Biol. Chem. 274, 29603-6 (1999).
40. 2+ current in mouse ventricular myocytes. Mol. Pharmacol. 56, 485-493 (1999).
41. Wiens, B. L., Nelspon, C. S. & Neve, K. A. Contribution of serine residues to constitutive and agonist-induced signaling via the D2s dopamine receptor: evidence for multiple, agonist-specific active conformations. Mol. Pharmacol. 54, 435-441 (1998).
42. 5]enkephalin. J. Biol. Chem. 276, 37770-37786 (2001).
43. Christmanson, L., Westermark, P., & Bertsholtz C. Islet amyloid polypeptide stimulates cyclic AMP accumulation via the porcine calcitonin receptor. Biochem. Biophys. Res. Commun. 205, 1226-1235 (1994).
44. Stephenson, R. P. A modification of receptor theory. Br. J. Pharmacol. 11, 379-391 (1956).
45. Costa, T. & Herz, A. Antagonists with negative intrinsic activity at δ-opioid receptors coupled to GTP-binding proteins. Proc. Natl Acad. Sci. USA 86, 7321-7325 (1989).
46. Pommier, B. et al. The cholecystokinB receptor is coupled to two effector pathways through pertussis toxin-sensitive and -insensitive G proteins. J. Neurochem. 73, 281-288 (1999).
47. 1A receptor as assessed with the cytosensor microphysiometer J. Pharmacol. Toxicol. Meth. 40, 47-55 (1999).
48. 1-adrenergic receptor: evidence for interaction with distinct conformations of 1-adrenergic receptor J. Pharmacol. Expt. Ther. 294, 923-932 (2000).
49. Thomas, W. G., Quian, H., Chang, C.-S. & Karnik, S. Agonist-induced phosphorylation of the angiotensin II (AT1A) receptor requires generation of a conformation that is distinct from the inositol phosphate-signaling state. J. Biol. Chem. 275, 2893-2900 (2000).
50. 5]enkephalin-μ-opioid complexes demonstrated by cyclic independent protein kinase phosphorylation. J. Neurochem. 71, 231-233(1998).
51. Blake, A. D., Bot, G., Freeman, J. C. & Reisine, T. Differential opioid agonist regulation of the mouse μ-opioid receptor. J. Biol. Chem. 272, 782-790 (1997).
52. van Hooft, J. A., Vijverberg, H. P. M. Selection of distinct conformational states of the 5-HT3 receptor by full and partial agonists. Br. J. Pharmacol. 117, 839-846 (1997).
53. Roettger, B. F. et al. Antagonist-stimulated internalization of the G protein-coupled cholecystokinin receptor Mol. Pharmacol. 51, 357-362 (1997).
54. Keith, D. E. et al. Morphine activates diploid receptors without causing their rapid internalization. J. Biol. Chem. 271, 19021-19024(1996).
55. Hunyady, L., Baukal, A. J., Balla, T. & Catt, K. J. Independence of type I angiotensin II receptor endocytosis from G protein coupling and signal transduction. J. Biol. Chem. 269, 24798-24804 (1994).
56. Vila-Coro, A. J., Mellado, M., Matrin de Ana, A., Martinez-A., C. & Rodriguez-Frade, J. M. Characterization of RANTES- and Aminooxypentane-RANTES-triggered desensitization signals reveals differences in recruitment of the G-protein-coupled receptor complex. J. Immunol. 163, 3037-3044(1999).
57. Dickenson, J. M. & Hill, S. J. Synergistic interactions between human transfected adenosine A1 receptors and endogenous cholecystokin receptors in CHO cells. Eur. J. Pharmacol. 302, 141-151 (1996).
58. Gerwins, P. & Fredholm, B. B. ATP and its metabolite adenosine act synergistically to mobilise intracellular calcium via the formation of inositol 1,4,5-triphosphate in a smooth muscle line. J. Biol. Chem. 267, 16081-16090 (1992).
59. 1 receptors and bradykinin receptors which act via different G-proteins synergistically raises inositol 1,4,5-triphosphate and intracellular calcium in DDT, MF-2 smooth muscle cells. Proc. Natl Acad. Sci. USA 89, 7330-7339 (1992).
60. 1MF-2 cells. Biochem. Soc. Trans. 22, 427S (1994).
61. AbdAlla S., Lother, H. & Quitterrer, U. AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407, 94-99 (2001).
62. Devi, L. A. Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking. Trends Pharmacol. Sci. 22, 532-537 (2001).
63. Jordan, B. A., Cvejic, S. & Devi, L. A. Opioids and their complicated receptor complexes. Neuropsychopharmacology 23, S5-S18 (2000).
64. Zhu, Y. et al. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24, 243-252 (1999).
65. Rocheville, M. et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288, 154-157 (2000).
66. i. Mol. Pharmacol. 62, 654-659 (2002).
67. 0. subtype of G proteins in SH-SY5Y cells. Br. J. Pharmacol. 128, 1181-1188 (1999).
68. Albert, P. R. & Robillard, L. G-protein specificity: Traffic direction required, Cell. Signal. 14, 407-418 (2002).
69. 1 receptor to phospholipase C in transfected CHO cells. Eur. J. Pharmacol, 355, 85-93 (1998).
70. Selbie L. A. & Hill, S. J. G protein-coupled-receptor cross-talk: the fine tuning of multiple receptor-signalling pathways. Trends Pharmacol. Sci. 19, 87-93 (1998).
71. Marinissen, M. J. & Gutkind, J. S. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol. Sci. 22, 368-376 (2001).
72. Ostrom, R. S. New determinants of receptor-effector coupling: trafficking and compartmentation in membrane microdomains. Mol. Pharmacol. 61, 473-476 (2002).
73. s. J. Pharmacol. Exp. Ther. 294, 407-412 (2000).
74. Rybin, V. O., Xu, X., Lisanti, M. P. & Steinberg, S. F. Differential targeting of β-adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae: A mechanism to functionally regulate the cAMP signaling pathway. J. Biol. Chem. 275, 41447-41453 (2000).
75. 2+ channel Cav1. 2. Science 293, 98-101 (2001).
76. 2-adrenergic receptor complex facilitates receptor phosphorylation and signaling. Curr. Biol. 10, 409-412 (2000).
77. Armour, S., Foord, S., Kenakin, T. P. & Chen, W-J. Pharmacological characterization of receptor activity modifying proteins (RAMPs) and the human calcitonin receptor J. Pharmacol. Toxicol. Methods 42, 217-224 (1999).
78. Fraser, N. J. et al. The amino terminus of receptor activity modifying proteins is a critical determinant of glycosylation state and ligand binding of calcitonin-like receptor. Mol. Pharmacol. 55, 1054-1059 (1999).
79. Foord, S. M. & Marshall, F. H. RAMPS: Accessory proteins for seven transmembrane domain receptors. Trends Pharmacol. Sci. 20, 184-187 (1999).
80. McLatchie, L. M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor Nature 393, 333-339(1998).
81. Christopoulos, G. et al. Multiple amylin receptors arise from receptor activity modifying protein interaction with the calcitonin receptor gene product. Mol. Pharmacol. 56, 235-242 (1999).
82. Christopoulos, A. et al. Novel receptor partners and function of receptor activity-modifying proteins. J. Biol. Chem. 278, 3293-3297 (2003).
83. 1A receptors to adenylyl cyclase. Mol. Pharmacol. 41, 999-1007(1992).
84. Cortes, S. F., Lemos, V. S., Corriu, C. & Stoclet, J. C. Changes in angiotensin II receptor density and calcium handling during proliferation in SHR aortic myocytes. Am. J. Physiol. 271, H2330-2338 (1996).
85. Hoel, N. L., Hansen-Schwartz, J. & Edvinsson, L. Selective up-regulation of 5-HT(1B/1D) receptors during organ culture of cerebral arteries. Neuroreport 12, 1605-1608 (2001).
86. Lelievre, V., Caigneaux, E., Muller, J. M. & Falcon, J. Extracellular adenosine deprivation induces epithelial differentiation of HT29 cells: Evidence for a concomitant adenosine A(1)/A(2) receptor balance regulation. Eur. J. Pharmacol. 10, 21-29 (2000).
87. Makino, I. et al. Phenotypic changes of adrenomedullin receptor components, RAMP2, and CRLR mRNA expression in cultured rat vascular smooth muscle cell. Biochem. Biophys. Res. Commun. 288, 515-520 (2001).
88. Bowers, C. W. & Dahm, L. M. Extracellular matrix regulates smooth muscle responses to substance P Proc. Natl Acad. Sci. USA 89, 8130-8134 (1992).
89. Kawase, T., Orikasa, M. & Suzuki, A. Starvation of clonal osteoblast-like cell line MOB 3-4-F2, down-regulates prostaglandin E2 receptors but increases cAMP response to prostaglandin E2. Cell Signal 3, 153-158 (1991).
90. Corriu, C., Andre, P., Schott, C., Michel, M. & Stoclet, J. C. ANG II receptor expression and function during phenotypic modulation of rat aortic smooth muscle cells. Am. J. Physiol. 266, H631-636 (1994).
91. Chakraborthy, M., Chatterjee, D., Kellokumpu, S., Rasmussen, H. & Baron, R. N. Cell cycle-dependent coupling of the calcitonin receptor to different G-proteins. Science, 251, 1078-1082 (1991).
92. Chen, W. J. et al. Expression cloning and receptor pharmacology of human calcitonin receptors from MCF-7 cells and their relationship to amylin receptors. Mol. Pharmacol. 52, 1164-1175 (1997).
93. Muff, R., Buhlmann, N., Fischer, J. A. & Born, W. An amylin receptor is revealed following co-transfection of a calcitonin receptor with receptor activity modifying proteins-1 or -3. Endocrinology 140, 2924-2927 (1999).
94. Tilakaratne N., Christopoulos, G., Zumpe, E. T., Foord, S. M. & Sexton, P. M. Amylin receptor phenotypes derived from human calcitonin receptor/RAMP coexpression exhibit pharmacological differences dependent on receptor isoform and host cell environment. J. Pharmacol. Exp. Ther. 294, 61-72 (2000)
95. 4-adrenoceptor' in mammalian heart. Clin. Exp. Pharmacol. Physiol. 24, 647-656(1997).
96. 1-adrenergic receptor. Am. J. Physiol. Endocrinol. Metab. 43, E199-E202 (2001).
97. 3-adrenergic-independent effects of CGP 12177 in brown adipose tissue. Mol. Pharmacol. 57, 252-258 (2000).
98. Traynor, J. Subtypes of μ-opioid receptor: fact or fiction. Trends Pharmacol. Sci. 10, 52-53 (1989).
99. Traynor, J. & Elliot, J. δ-opioid receptor subtypes and cross talk with μ-receptors. Trends Pharmacol. Sci. 14, 84-85 (1993).
100. Jordan, B. A. & Devi, L. A. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399, 697-700(1999).