Discovery and Development of Small Molecule Allosteric Modulators of Glycoprotein Hormone Receptors

Frontiers in Endocrinology

Volumn 6, Issue , 2015, Pages

  Nataraja, Selvaraj G ^a   Yu, Henry N ^a,b   Palmer, Stephen S ^a  

^a TocopheRx   (United States)

^b EMD Serono Research and Development Institute Inc   (United States)

Author keywords

follicle stimulating hormone; G protein coupled receptor; glycoprotein hormone receptors; leucine rich repeat; leutinizing hormone chorionic gonadotropin; small molecule allosteric modulators; thyroid stimulating hormone

Indexed keywords

EID: 85003964686     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2015.00142     Document Type: Review

References (172)

1. Albanese C Colin IM Crowley WF Ito M Pestell RG Weiss J et al. The gonadotropin genes: evolution of distinct mechanisms for hormonal control. Recent Prog Horm Res (1996) 51:23–58.8701081
2. Ryan RJ Charlesworth MC McCormick DJ Milius RP Keutmann HT. The glycoprotein hormones: recent studies of structure-function relationships. FASEB J (1988) 2(11):2661–9.2456242
3. Pierce JG Parsons TF. Glycoprotein hormones: structure and function. Annu Rev Biochem (1981) 50:465–95.10.1146/annurev.bi.50.070181.002341
4. Pierce JG Faith MR Giudice LC Reeve JR. Structure and structure-function relationships in glycoprotein hormones. Ciba Found Symp (1976) 41:225–50.780075
5. Stockell Hartree A Renwick AG. Molecular structures of glycoprotein hormones and functions of their carbohydrate components. Biochem J (1992) 287(Pt 3):665–79.10.1042/bj2870665
6. Canfield RE O’Connor JF. Biological markers on human pregnancy. Biomed Environ Sci (1991) 4(1–2):56–68.1910601
7. Hearn JP Webley GE Gidley-Baird AA. Chorionic gonadotrophin and embryo-maternal recognition during the peri-implantation period in primates. J Reprod Fertil (1991) 92(2):497–509.10.1530/jrf.0.09204971886105
8. Fiddes JC Goodman HM. The cDNA for the beta-subunit of human chorionic gonadotropin suggests evolution of a gene by readthrough into the 3’-­untranslated region. Nature (1980) 286(5774):684–7.10.1038/286684a06774259
9. Jameson JL Lindell CM Habener JF. Evolution of different transcriptional start sites in the human luteinizing hormone and chorionic gonadotropin beta-subunit genes. DNA (1986) 5(3):227–34.10.1089/dna.1986.5.2272424697
10. Li MD Ford JJ. A comprehensive evolutionary analysis based on nucleotide and amino acid sequences of the alpha- and beta-subunits of glycoprotein hormone gene family. J Endocrinol (1998) 156(3):529–42.10.1677/joe.0.15605299582510
11. Boime I Ben-Menahem D. Glycoprotein hormone structure-function and analog design. Recent Prog Horm Res (1999) 54:271–88.10548880
12. Sairam MR. Role of carbohydrates in glycoprotein hormone signal transduction. FASEB J (1989) 3(8):1915–26.2542111
13. Matzuk MM Boime I. Mutagenesis and gene transfer define site-specific roles of the gonadotropin oligosaccharides. Biol Reprod (1989) 40(1):48–53.10.1095/biolreprod40.1.482647161
14. Fournier T Guibourdenche J Evain-Brion D. Review: hCGs: different sources of production, different glycoforms and functions. Placenta (2015) 36(Suppl 1):S60–5.10.1016/j.placenta.2015.02.00225707740
15. Fares F. The role of O-linked and N-linked oligosaccharides on the structure-function of glycoprotein hormones: development of agonists and antagonists. Biochim Biophys Acta (2006) 1760(4):560–7.10.1016/j.bbagen.2005.12.02216527410
16. Bishop LA Robertson DM Cahir N Schofield PR. Specific roles for the asparagine-linked carbohydrate residues of recombinant human follicle stimulating hormone in receptor binding and signal transduction. Mol Endocrinol (1994) 8(6):722–31.10.1210/me.8.6.7227935488
17. Fares FA Gruener N Kraiem Z. The role of the asparagine-linked oligosaccharides of the alpha-subunit in human thyrotropin bioactivity. Endocrinology (1996) 137(2):555–60.10.1210/endo.137.2.85938028593802
18. Matzuk MM Keene JL Boime I. Site specificity of the chorionic gonadotropin N-linked oligosaccharides in signal transduction. J Biol Chem (1989) 264(5):2409–14.2536708
19. Ulloa-Aguirre A Timossi C Damian-Matsumura P Dias JA. Role of glycosylation in function of follicle-stimulating hormone. Endocrine (1999) 11(3):205–15.10.1385/ENDO:11:3:20510786817
20. Kalyan NK Bahl OP. Role of carbohydrate in human chorionic gonadotropin. Effect of deglycosylation on the subunit interaction and on its in vitro and in vivo biological properties. J Biol Chem (1983) 258(1):67–74.
21. Davis JS Kumar TR May JV Bousfield GR. Naturally occurring follicle-­stimulating hormone glycosylation variants. J Glycomics Lipidomics (2014) 4(1):e117.10.4172/2153-0637.1000e117
22. Jiang C Hou X Wang C May JV Butnev VY Bousfield GR et al. Hypoglycosylated hFSH has greater bioactivity than fully glycosylated recombinant hFSH in human granulosa cells. J Clin Endocrinol Metab (2015) 100(6):E852–60.10.1210/jc.2015-131725915568
23. Crochet JR Shah AA Schomberg DW Price TM. Hyperglycosylated human chorionic gonadotropin does not increase progesterone production by luteinized granulosa cells. J Clin Endocrinol Metab (2012) 97(9):E1741–4.10.1210/jc.2012-202722745244
24. Clayton RN. Mechanism of GnRH action in gonadotrophs. Hum Reprod (1988) 3(4):479–83.2839540
25. Plant TM. Hypothalamic control of the pituitary-gonadal axis in higher primates: key advances over the last two decades. J Neuroendocrinol (2008) 20(6):719–26.10.1111/j.1365-2826.2008.01708.x18601694
26. Evans JJ. Modulation of gonadotropin levels by peptides acting at the anterior pituitary gland. Endocr Rev (1999) 20(1):46–67.10.1210/edrv.20.1.035510047973
27. Padmanabhan V Karsch FJ Lee JS. Hypothalamic, pituitary and gonadal regulation of FSH. Reprod Suppl (2002) 59:67–82.12698974
28. Shupnik MA. Gonadotropin gene modulation by steroids and gonadotropin-releasing hormone. Biol Reprod (1996) 54(2):279–86.10.1095/biolreprod54.2.2798788177
29. Channing CP Hillensjo T Schaerf FW. Hormonal control of oocyte meiosis, ovulation and luteinization in mammals. Clin Endocrinol Metab (1978) 7(3):601–24.10.1016/S0300-595X(78)80011-5215357
30. Schwartz NB McCormack CE. Reproduction: gonadal function and its regulation. Annu Rev Physiol (1972) 34:425–72.10.1146/annurev.ph.34.030172.002233
31. de Kretser DM. Endocrinology of male infertility. Br Med Bull (1979) 35(2):187–92.
32. Chiamolera MI Wondisford FE. Minireview: thyrotropin-releasing hormone and the thyroid hormone feedback mechanism. Endocrinology (2009) 150(3):1091–6.10.1210/en.2008-179519179434
33. Persani L. Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity. Thyroid (1998) 8(10):941–6.10.1089/thy.1998.8.9419827663
34. Brabant G Ocran K Ranft U von zur Muhlen A Hesch RD. Physiological regulation of thyrotropin. Biochimie (1989) 71(2):293–301.10.1016/0300-9084(89)90066-72495828
35. Licht P Denver RJ. Regulation of pituitary thyrotropin secretion. Prog Clin Biol Res (1990) 342:427–32.2200023
36. Postiglione MP Parlato R Rodriguez-Mallon A Rosica A Mithbaokar P Maresca M et al. Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland. Proc Natl Acad Sci U S A (2002) 99(24):15462–7.10.1073/pnas.24232899912432093
37. Bahn RS. Autoimmunity and Graves’ disease. Clin Pharmacol Ther (2012) 91(4):577–9.10.1038/clpt.2012.1022434030
38. Davies TF Ando T Lin RY Tomer Y Latif R. Thyrotropin receptor-­associated diseases: from adenomata to Graves disease. J Clin Invest (2005) 115(8):1972–83.10.1172/JCI2603116075037
39. Dong YH Fu DG. Autoimmune thyroid disease: mechanism, genetics and current knowledge. Eur Rev Med Pharmacol Sci (2014) 18(23):3611–8.25535130
40. Muldoon BT Mai VQ Burch HB. Management of Graves’ disease: an overview and comparison of clinical practice guidelines with actual practice trends. Endocrinol Metab Clin North Am (2014) 43(2):495–516.10.1016/j.ecl.2014.02.00124891174
41. Weetman AP. Thyroid abnormalities. Endocrinol Metab Clin North Am (2014) 43(3):781–90.10.1016/j.ecl.2014.05.00625169567
42. Fredriksson R Schioth HB. The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol (2005) 67(5):1414–25.10.1124/mol.104.00900115687224
43. Overington JP Al-Lazikani B Hopkins AL. How many drug targets are there? Nat Rev Drug Discov (2006) 5(12):993–6.10.1038/nrd2199
44. Wise A Gearing K Rees S. Target validation of G-protein coupled receptors. Drug Discov Today (2002) 7(4):235–46.10.1016/S1359-6446(01)02131-611839521
45. Kristiansen K. Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol Ther (2004) 103(1):21–80.10.1016/j.pharmthera.2004.05.00215251227
46. Premont RT Gainetdinov RR. Physiological roles of G protein-coupled receptor kinases and arrestins. Annu Rev Physiol (2007) 69:511–34.10.1146/annurev.physiol.69.022405.15473117305472
47. Venkatakrishnan AJ Deupi X Lebon G Tate CG Schertler GF Babu MM. Molecular signatures of G-protein-coupled receptors. Nature (2013) 494(7436):185–94.10.1038/nature1189623407534
48. Van Loy T Vandersmissen HP Van Hiel MB Poels J Verlinden H Badisco L et al. Comparative genomics of leucine-rich repeats containing G protein-coupled receptors and their ligands. Gen Comp Endocrinol (2008) 155(1):14–21.10.1016/j.ygcen.2007.06.02217706217
49. Alexander SP Benson HE Faccenda E Pawson AJ Sharman JL Spedding M et al. The concise guide to PHARMACOLOGY 2013/14: G protein-coupled receptors. Br J Pharmacol (2013) 170(8):1459–581.10.1111/bph.1244524517644
50. Kumar KK Burgess AW Gulbis JM. Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells. Protein Sci (2014) 23(5):551–65.10.1002/pro.244624677446
51. Jiang X Dias JA He X. Structural biology of glycoprotein hormones and their receptors: insights to signaling. Mol Cell Endocrinol (2014) 382(1):424–51.10.1016/j.mce.2013.08.02124001578
52. Kleinau G Krause G. Thyrotropin and homologous glycoprotein hormone receptors: structural and functional aspects of extracellular signaling mechanisms. Endocr Rev (2009) 30(2):133–51.10.1210/er.2008-004419176466
53. Ulloa-Aguirre A Crepieux P Poupon A Maurel MC Reiter E. Novel pathways in gonadotropin receptor signaling and biased agonism. Rev Endocr Metab Disord (2011) 12(4):259–74.10.1007/s11154-011-9176-221526415
54. Ulloa-Aguirre A Zarinan T Pasapera AM Casas-Gonzalez P Dias JA. Multiple facets of follicle-stimulating hormone receptor function. Endocrine (2007) 32(3):251–63.10.1007/s12020-008-9041-618246451
55. Krishnamurthy H Galet C Ascoli M. The association of arrestin-3 with the follitropin receptor depends on receptor activation and phosphorylation. Mol Cell Endocrinol (2003) 204(1–2):127–40.10.1016/S0303-7207(03)00088-112850288
56. Tranchant T Durand G Gauthier C Crepieux P Ulloa-Aguirre A Royere D et al. Preferential beta-arrestin signalling at low receptor density revealed by functional characterization of the human FSH receptor A189 V mutation. Mol Cell Endocrinol (2011) 331(1):109–18.10.1016/j.mce.2010.08.01620801186
57. Ulloa-Aguirre A Dias JA Bousfield G Huhtaniemi I Reiter E. Trafficking of the follitropin receptor. Methods Enzymol (2013) 521:17–45.10.1016/B978-0-12-391862-8.00002-823351732
58. Hunzicker-Dunn M Maizels ET. FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A. Cell Signal (2006) 18(9):1351–9.10.1016/j.cellsig.2006.02.01116616457
59. Walker WH Cheng J. FSH and testosterone signaling in sertoli cells. Reproduction (2005) 130(1):15–28.10.1530/rep.1.0035815985628
60. Landomiel F Gallay N Jegot G Tranchant T Durand G Bourquard T et al. Biased signalling in follicle stimulating hormone action. Mol Cell Endocrinol (2014) 382(1):452–9.10.1016/j.mce.2013.09.03524121199
61. Lapthorn AJ Harris DC Littlejohn A Lustbader JW Canfield RE Machin KJ et al. Crystal structure of human chorionic gonadotropin. Nature (1994) 369(6480):455–61.10.1038/369455a08202136
62. Wu H Lustbader JW Liu Y Canfield RE Hendrickson WA. Structure of human chorionic gonadotropin at 2.6 A resolution from MAD analysis of the selenomethionyl protein. Structure (1994) 2(6):545–58.10.1016/S0969-2126(00)00054-X7922031
63. Fox KM Dias JA Roey PV. Three-dimensional structure of human follicle-stimulating hormone. Mol Endocrinol (2001) 15(3):378–89.10.1210/mend.15.3.060311222739
64. Campbell RK Dean-Emig DM Moyle WR. Conversion of human choriogonadotropin into a follitropin by protein engineering. Proc Natl Acad Sci U S A (1991) 88(3):760–4.10.1073/pnas.88.3.7601899483
65. Dias JA Zhang Y Liu X. Receptor binding and functional properties of chimeric human follitropin prepared by an exchange between a small hydrophilic intercysteine loop of human follitropin and human lutropin. J Biol Chem (1994) 269(41):25289–94.7929221
66. Huang J Ujihara M Xia H Chen F Yoshida H Puett D. Mutagenesis of the ‘determinant loop’ region of human choriogonadotropin beta. Mol Cell Endocrinol (1993) 90(2):211–8.10.1016/0303-7207(93)90154-C7684341
67. Chen F Puett D. Contributions of arginines-43 and -94 of human choriogonadotropin beta to receptor binding and activation as determined by oligonucleotide-based mutagenesis. Biochemistry (1991) 30(42):10171–5.10.1021/bi00106a0141931947
68. Weiss J Axelrod L Whitcomb RW Harris PE Crowley WF Jameson JL. Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. N Engl J Med (1992) 326(3):179–83.10.1056/NEJM199201163260306
69. Roth KE Dias JA. Scanning-alanine mutagenesis of long loop residues 33-53 in follicle stimulating hormone beta subunit. Mol Cell Endocrinol (1995) 109(2):143–9.10.1016/0303-7207(95)03494-R7664976
70. Chen F Wang Y Puett D. The carboxy-terminal region of the glycoprotein hormone alpha-subunit: contributions to receptor binding and signaling in human chorionic gonadotropin. Mol Endocrinol (1992) 6(6):914–9.10.1210/me.6.6.9141379673
71. Grossmann M Szkudlinski MW Zeng H Kraiem Z Ji I Tropea JE et al. Role of the carboxy-terminal residues of the alpha-subunit in the expression and bioactivity of human thyroid-stimulating hormone. Mol Endocrinol (1995) 9(8):948–58.10.1210/mend.9.8.74769927476992
72. Sen Gupta C Dighe RR. Biological activity of single chain chorionic gonadotropin, hCGalphabeta, is decreased upon deletion of five carboxyl terminal amino acids of the alpha subunit without affecting its receptor binding. J Mol Endocrinol (2000) 24(2):157–64.10.1677/jme.0.024015710750017
73. Jiang X Dreano M Buckler DR Cheng S Ythier A Wu H et al. Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions. Structure (1995) 3(12):1341–53.10.1016/S0969-2126(01)00272-68747461
74. Kajava AV Vassart G Wodak SJ. Modeling of the three-dimensional structure of proteins with the typical leucine-rich repeats. Structure (1995) 3(9):867–77.10.1016/S0969-2126(01)00222-28535781
75. Moyle WR Campbell RK Rao SN Ayad NG Bernard MP Han Y et al. Model of human chorionic gonadotropin and lutropin receptor interaction that explains signal transduction of the glycoprotein hormones. J Biol Chem (1995) 270(34):20020–31.10.1074/jbc.270.34.200207650020
76. Fan QR Hendrickson WA. Structure of human follicle-stimulating hormone in complex with its receptor. Nature (2005) 433(7023):269–77.10.1038/nature0320615662415
77. Jiang X Liu H Chen X Chen PH Fischer D Sriraman V et al. Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. Proc Natl Acad Sci U S A (2012) 109(31):12491–6.10.1073/pnas.120664310922802634
78. Sanders J Chirgadze DY Sanders P Baker S Sullivan A Bhardwaja A et al. Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid (2007) 17(5):395–410.10.1089/thy.2007.004117542669
79. Kleinau G Neumann S Gruters A Krude H Biebermann H. Novel insights on thyroid-stimulating hormone receptor signal transduction. Endocr Rev (2013) 34(5):691–724.10.1210/er.2012-107223645907
80. Xu JG Huang C Yang Z Jin M Fu P Zhang N et al. Crystal structure of LGR4-Rspo1 complex: insights into the divergent mechanisms of ligand recognition by leucine-rich repeat G-protein-coupled receptors (LGRs). J Biol Chem (2015) 290(4):2455–65.10.1074/jbc.M114.59913425480784
81. Agrawal G Dighe RR. Critical involvement of the hinge region of the follicle-stimulating hormone receptor in the activation of the receptor. J Biol Chem (2009) 284(5):2636–47.10.1074/jbc.M80819920019029293
82. Dias JA Van Roey P. Structural biology of human follitropin and its receptor. Arch Med Res (2001) 32(6):510–9.10.1016/S0188-4409(01)00333-211750726
83. Mizutori Y Chen CR McLachlan SM Rapoport B. The thyrotropin receptor hinge region is not simply a scaffold for the leucine-rich domain but contributes to ligand binding and signal transduction. Mol Endocrinol (2008) 22(5):1171–82.10.1210/me.2007-040718218728
84. Mueller S Jaeschke H Gunther R Paschke R. The hinge region: an important receptor component for GPHR function. Trends Endocrinol Metab (2010) 21(2):111–22.10.1016/j.tem.2009.09.00119819720
85. Szkudlinski MW Fremont V Ronin C Weintraub BD. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev (2002) 82(2):473–502.10.1152/physrev.00031.200111917095
86. Zoenen M Urizar E Swillens S Vassart G Costagliola S. Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers. Nat Commun (2012) 3:1007.10.1038/ncomms199122893131
87. Costagliola S Panneels V Bonomi M Koch J Many MC Smits G et al. Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors. EMBO J (2002) 21(4):504–13.10.1093/emboj/21.4.50411847099
88. Bonomi M Busnelli M Persani L Vassart G Costagliola S. Structural differences in the hinge region of the glycoprotein hormone receptors: evidence from the sulfated tyrosine residues. Mol Endocrinol (2006) 20(12):3351–63.10.1210/me.2005-052116901970
89. Guan R Feng X Wu X Zhang M Zhang X Hebert TE et al. Bioluminescence resonance energy transfer studies reveal constitutive dimerization of the human lutropin receptor and a lack of correlation between receptor activation and the propensity for dimerization. J Biol Chem (2009) 284(12):7483–94.10.1074/jbc.M80915020019147490
90. Urizar E Montanelli L Loy T Bonomi M Swillens S Gales C et al. Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity. EMBO J (2005) 24(11):1954–64.10.1038/sj.emboj.760068615889138
91. Segaloff DL. Regulatory processes governing the cell surface expression of LH and FSH receptors. Subcell Biochem (2012) 63:113–29.10.1007/978-94-007-4765-4_723161136
92. Guan R Wu X Feng X Zhang M Hebert TE Segaloff DL. Structural determinants underlying constitutive dimerization of unoccupied human follitropin receptors. Cell Signal (2010) 22(2):247–56.10.1016/j.cellsig.2009.09.02319800402
93. Ji I Lee C Jeoung M Koo Y Sievert GA Ji TH. Trans-activation of mutant follicle-stimulating hormone receptors selectively generates only one of two hormone signals. Mol Endocrinol (2004) 18(4):968–78.10.1210/me.2003-044314726491
94. Lee C Ji I Ryu K Song Y Conn PM Ji TH. Two defective heterozygous luteinizing hormone receptors can rescue hormone action. J Biol Chem (2002) 277(18):15795–800.10.1074/jbc.M11181820011859079
95. Rivero-Muller A Chou YY Ji I Lajic S Hanyaloglu AC Jonas K et al. Rescue of defective G protein-coupled receptor function in vivo by intermolecular cooperation. Proc Natl Acad Sci U S A (2010) 107(5):2319–24.10.1073/pnas.090669510620080658
96. Jonas KC Fanelli F Huhtaniemi IT Hanyaloglu AC. Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies. J Biol Chem (2015) 290(7):3875–92.10.1074/jbc.M114.62249825516594
97. Mazurkiewicz JE Herrick-Davis K Barroso M Ulloa-Aguirre A Lindau-Shepard B Thomas RM et al. Single-molecule analyses of fully functional fluorescent protein-tagged follitropin receptor reveal homodimerization and specific heterodimerization with lutropin receptor. Biol Reprod (2015) 92(4):100.10.1095/biolreprod.114.12578125761594
98. Jiang X Fischer D Chen X McKenna SD Liu H Sriraman V et al. Evidence for follicle-stimulating hormone receptor as a functional trimer. J Biol Chem (2014) 289(20):14273–82.10.1074/jbc.M114.54959224692546
99. Conn PJ Christopoulos A Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov (2009) 8(1):41–54.10.1038/nrd276019116626
100. Changeux JP. Allosteric receptors: from electric organ to cognition. Annu Rev Pharmacol Toxicol (2010) 50:1–38.10.1146/annurev.pharmtox.010909.10574120055696
101. Bridges TM Lindsley CW. G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem Biol (2008) 3(9):530–41.10.1021/cb800116f18652471
102. De Amici M Dallanoce C Holzgrabe U Trankle C Mohr K. Allosteric ligands for G protein-coupled receptors: a novel strategy with attractive therapeutic opportunities. Med Res Rev (2010) 30(3):463–549.10.1002/med.2016619557759
103. Keov P Sexton PM Christopoulos A. Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology (2011) 60(1):24–35.10.1016/j.neuropharm.2010.07.01020637785
104. Wang CI Lewis RJ. Emerging opportunities for allosteric modulation of G-protein coupled receptors. Biochem Pharmacol (2013) 85(2):153–62.10.1016/j.bcp.2012.09.00122975406
105. Rees S Morrow D Kenakin T. GPCR drug discovery through the exploitation of allosteric drug binding sites. Receptors Channels (2002) 8(5–6):261–8.10.1080/1060682021464012690954
106. Burford NT Watson J Bertekap R Alt A. Strategies for the identification of allosteric modulators of G-protein-coupled receptors. Biochem Pharmacol (2011) 81(6):691–702.10.1016/j.bcp.2010.12.01221184747
107. Hansen RB Kavanaugh A. Novel treatments with small molecules in psoriatic arthritis. Curr Rheumatol Rep (2014) 16(9):443.10.1007/s11926-014-0443-625027606
108. Lundquist LM Cole SW Sikes ML. Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop (2014) 5(4):504–11.10.5312/wjo.v5.i4.50425232526
109. Lorefice L Fenu G Frau J Coghe GC Marrosu MG Cocco E. Oral agents in multiple sclerosis. Antiinflamm Antiallergy Agents Med Chem (2015) 14(1):15–25.10.2174/187152301499915041513022425924620
110. Safavi M Nikfar S Abdollahi M. A systematic review of drugs in late-stage development for the treatment of multiple sclerosis: a focus on oral synthetic drugs. Inflamm Allergy Drug Targets (2015) 13(6):351–66.10.2174/187152811466615052910261326021323
111. Brynhildsen J. Combined hormonal contraceptives: prescribing patterns, compliance, and benefits versus risks. Ther Adv Drug Saf (2014) 5(5):201–13.10.1177/204209861454885725360241
112. Hannaford PC. Combined oral contraceptives: do we know all of their effects? Contraception (1995) 51(6):325–7.10.1016/0010-7824(95)00095-R7554970
113. Thomin A Keller V Darai E Chabbert-Buffet N. Consequences of emergency contraceptives: the adverse effects. Expert Opin Drug Saf (2014) 13(7):893–902.10.1517/14740338.2014.92167824918174
114. Latif R Ali MR Ma R David M Morshed SA Ohlmeyer M et al. New small molecule agonists to the thyrotropin receptor. Thyroid (2015) 25(1):51–62.10.1089/thy.2014.011925333622
115. Bonger KM van den Berg RJ Knijnenburg AD Heitman LH van Koppen CJ Timmers CM et al. Discovery of selective luteinizing hormone receptor agonists using the bivalent ligand method. ChemMedChem (2009) 4(7):1189–95.10.1002/cmdc.20090005819475639
116. van Straten NC Schoonus-Gerritsma GG van Someren RG Draaijer J Adang AE Timmers CM et al. The first orally active low molecular weight agonists for the LH receptor: thienopyr(im)idines with therapeutic potential for ovulation induction. Chembiochem (2002) 3(10):1023–6.10.1002/1439-7633(20021004)3:10<1023::AID-CBIC1023>3.0.CO;2-9
117. Yu HN Richardson TE Nataraja S Fischer DJ Sriraman V Jiang X et al. Discovery of substituted benzamides as follicle stimulating hormone receptor allosteric modulators. Bioorg Med Chem Lett (2014) 24(9):2168–72.10.1016/j.bmcl.2014.03.01824685543
118. Kenakin TP. Cellular assays as portals to seven-transmembrane receptor-based drug discovery. Nat Rev Drug Discov (2009) 8(8):617–26.10.1038/nrd283819609267
119. Dias JA Bonnet B Weaver BA Watts J Kluetzman K Thomas RM et al. A negative allosteric modulator demonstrates biased antagonism of the follicle stimulating hormone receptor. Mol Cell Endocrinol (2011) 333(2):143–50.10.1016/j.mce.2010.12.02321184806
120. Sriraman V Denis D de Matos D Yu H Palmer S Nataraja S. Investigation of a thiazolidinone derivative as an allosteric modulator of follicle stimulating hormone receptor: evidence for its ability to support follicular development and ovulation. Biochem Pharmacol (2014) 89(2):266–75.10.1016/j.bcp.2014.02.02324630928
121. Arey BJ. Allosteric modulators of glycoprotein hormone receptors: discovery and therapeutic potential. Endocrine (2008) 34(1–3):1–10.10.1007/s12020-008-9098-218956257
122. Guo T. Small molecule agonists and antagonists for the LH and FSH receptors. Expert Opin Ther Pat (2005) 15(11):1555–64.10.1517/13543776.15.11.1555
123. van Straten N Timmers CM. Non-Peptide ligands for the gonadotropin receptors. Annu Rep Med Chem (2009) 44:171–88.10.1016/S0065-7743(09)04408-X
124. El Tayer N., Reddy A., Buckler D S. M, Inventors; Applied Research Systems ARS Holding N.A., assignee. FSH Mimetics for the Treatment of Infertility. Unites States patent US 6,235,755 (2001).
125. Arey BJ Yanofsky SD Claudia Perez M Holmes CP Wrobel J Gopalsamy A et al. Differing pharmacological activities of thiazolidinone analogs at the FSH receptor. Biochem Biophys Res Commun (2008) 368(3):723–8.10.1016/j.bbrc.2008.01.11918252197
126. Wrobel J Jetter J Kao W Rogers J Di L Chi J et al. 5-Alkylated thiazolidinones as follicle-stimulating hormone (FSH) receptor agonists. Bioorg Med Chem (2006) 14(16):5729–41.10.1016/j.bmc.2006.04.01216675221
127. Yanofsky SD Shen ES Holden F Whitehorn E Aguilar B Tate E et al. Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists. J Biol Chem (2006) 281(19):13226–33.10.1074/jbc.M60060120016540466
128. Pelletier JC Rogers J Wrobel J Perez MC Shen ES. Preparation of highly substituted gamma-lactam follicle stimulating hormone receptor agonists. Bioorg Med Chem (2005) 13(21):5986–95.10.1016/j.bmc.2005.07.02516099664
129. Guo T Adang AE Dolle RE Dong G Fitzpatrick D Geng P et al. Small molecule biaryl FSH receptor agonists. Part 1: lead discovery via encoded combinatorial synthesis. Bioorg Med Chem Lett (2004) 14(7):1713–6.10.1016/j.bmcl.2004.01.04315026056
130. Guo T Adang AE Dong G Fitzpatrick D Geng P Ho KK et al. Small molecule biaryl FSH receptor agonists. Part 2: lead optimization via parallel synthesis. Bioorg Med Chem Lett (2004) 14(7):1717–20.10.1016/j.bmcl.2004.01.04315026057
131. Magar S., Goutopoulos A Liao Y Schwarz M R.J. T, Inventors; Merck Serono SA, assignee. Piperazine Derivatives and Methods of Use. United States patent US WO2004/031182 (2004).
132. van Straten NC van Berkel TH Demont DR Karstens WJ Merkx R Oosterom J et al. Identification of substituted 6-amino-4-phenyltetrahydroquinoline derivatives: potent antagonists for the follicle-stimulating hormone receptor. J Med Chem (2005) 48(6):1697–700.10.1021/jm049676l15771412
133. Grima Poveda PM Karstens Willem FJ Timmers CM Inventors; N.V. Organon, assignee. 4-Phenyl-5-Oxo-1,4,5,6,7,8-Hexahydroquinoline Derivatives for the Treatment of Infertility. United States patent US 8,022,218 (2006).
134. Hanssen RGJM Timmers CM Inventors. Preparation of Thienopyrimidines with Combined FSH and LH Activity (2003).
135. van Koppen CJ Verbost PM van de Lagemaat R Karstens WJ Loozen HJ van Achterberg TA et al. Signaling of an allosteric, nanomolar potent, low molecular weight agonist for the follicle-stimulating hormone receptor. Biochem Pharmacol (2013) 85(8):1162–70.10.1016/j.bcp.2013.02.00123415902
136. Timmers CM Karstens WF Grima Poveda PM Inventors; N.V. Organon, assignee. 4-Phenyl-5-Oxo-1,4,5,6,7,8-Hexahydroquinoline Derivatives as Medicaments for the Treatment of Infertility. United States patent US WO2006/117370 (2006).
137. Bahamondes L Bahamondes MV. New and emerging contraceptives: a state-of-the-art review. Int J Womens Health (2014) 6:221–34.10.2147/IJWH.S4681124570597
138. Warren AM Gurvich C Worsley R Kulkarni J. A systematic review of the impact of oral contraceptives on cognition. Contraception (2014) 90(2):111–6.10.1016/j.contraception.2014.03.01524856205
139. Palermo R. Differential actions of FSH and LH during folliculogenesis. Reprod Biomed Online (2007) 15(3):326–37.10.1016/S1472-6483(10)60347-117854533
140. Vegetti W Alagna F. FSH and folliculogenesis: from physiology to ovarian stimulation. Reprod Biomed Online (2006) 12(6):684–94.10.1016/S1472-6483(10)61080-216792843
141. Weinbauer GF Behre HM Fingscheidt U Nieschlag E. Human follicle-­stimulating hormone exerts a stimulatory effect on spermatogenesis, testicular size, and serum inhibin levels in the gonadotropin-releasing hormone antagonist-treated nonhuman primate (Macaca fascicularis). Endocrinology (1991) 129(4):1831–9.10.1210/endo-129-4-18311915071
142. Moudgal NR Sairam MR Krishnamurthy HN Sridhar S Krishnamurthy H Khan H. Immunization of male bonnet monkeys (M. radiata) with a recombinant FSH receptor preparation affects testicular function and fertility. Endocrinology (1997) 138(7):3065–8.10.1210/endo.138.7.53819202254
143. Arey BJ Deecher DC Shen ES Stevis PE Meade EH Jr Wrobel J et al. Identification and characterization of a selective, nonpeptide follicle-stimulating hormone receptor antagonist. Endocrinology (2002) 143(10):3822–9.10.1210/en.2002-22037212239093
144. Coats SJ Fitzpatrick LJ Hlasta DJ Lanter CL Macielag MJ Pan K et al. Inventors; Ortho-McNeill Pharmaceutical, Inc., assignee. Substituted Aminoalkylamide Derivatives as Antagonists of Follicle Stimulating Hormone. United States patent US 6,583,179 B2 (2003).
145. Bonger KM Hoogendoorn S van Koppen CJ Timmers CM Overkleeft HS van der Marel GA. Synthesis and pharmacological evaluation of dimeric follicle-stimulating hormone receptor antagonists. ChemMedChem (2009) 4(12):2098–102.10.1002/cmdc.20090034419902448
146. van de Lagemaat R van Koppen CJ Krajnc-Franken MA Folmer BJ van Diepen HA Mulders SM et al. Contraception by induction of luteinized unruptured follicles with short-acting low molecular weight FSH receptor agonists in female animal models. Reproduction (2011) 142(6):893–905.10.1530/REP-11-023421930683
147. Dias JA Campo B Weaver BA Watts J Kluetzman K Thomas RM et al. Inhibition of follicle-stimulating hormone-induced preovulatory follicles in rats treated with a nonsteroidal negative allosteric modulator of follicle-stimulating hormone receptor. Biol Reprod (2014) 90(1):19.10.1095/biolreprod.113.10939724285717
148. Newton CL Whay AM McArdle CA Zhang M van Koppen CJ van de Lagemaat R et al. Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist. Proc Natl Acad Sci U S A (2011) 108(17):7172–6.10.1073/pnas.101572310821482767
149. Jorand-Lebrun C Brondyk B Lin J Magar S Murray R Reddy A et al. Identification, synthesis, and biological evaluation of novel pyrazoles as low molecular weight luteinizing hormone receptor agonists. Bioorg Med Chem Lett (2007) 17(7):2080–5.10.1016/j.bmcl.2006.12.06217321742
150. Bonger KM Hoogendoorn S van Koppen CJ Timmers CM van der Marel GA Overkleeft HS. Development of selective LH receptor agonists by heterodimerization with a FSH receptor antagonist. ACS Med Chem Lett (2011) 2(1):85–9.10.1021/ml100229v24900256
151. van de Lagemaat R Timmers CM Kelder J van Koppen C Mosselman S Hanssen RG. Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor. Hum Reprod (2009) 24(3):640–8.10.1093/humrep/den41219088107
152. van Koppen CJ Zaman GJ Timmers CM Kelder J Mosselman S van de Lagemaat R et al. A signaling-selective, nanomolar potent allosteric low molecular weight agonist for the human luteinizing hormone receptor. Naunyn Schmiedebergs Arch Pharmacol (2008) 378(5):503–14.10.1007/s00210-008-0318-318551279
153. Binder H Dittrich R Einhaus F Krieg J Muller A Strauss R et al. Update on ovarian hyperstimulation syndrome: part 1 – incidence and pathogenesis. Int J Fertil Womens Med (2007) 52(1):11–26.17987884
154. Vlahos NF Gregoriou O. Prevention and management of ovarian hyperstimulation syndrome. Ann N Y Acad Sci (2006) 1092:247–64.10.1196/annals.1365.02117308149
155. Kashyap S Parker K Cedars MI Rosenwaks Z. Ovarian hyperstimulation syndrome prevention strategies: reducing the human chorionic gonadotropin trigger dose. Semin Reprod Med (2010) 28(6):475–85.10.1055/s-0030-126567421082506
156. van de Lagemaat R Raafs BC van Koppen C Timmers CM Mulders SM Hanssen RG. Prevention of the onset of ovarian hyperstimulation syndrome (OHSS) in the rat after ovulation induction with a low molecular weight agonist of the LH receptor compared with hCG and rec-LH. Endocrinology (2011) 152(11):4350–7.10.1210/en.2011-107721896671
157. Gerrits M Mannaerts B Kramer H Addo S Hanssen R. First evidence of ovulation induced by oral LH agonists in healthy female volunteers of reproductive age. J Clin Endocrinol Metab (2013) 98(4):1558–66.10.1210/jc.2012-340423515453
158. Heitman LH Narlawar R de Vries H Willemsen MN Wolfram D Brussee J et al. Substituted terphenyl compounds as the first class of low molecular weight allosteric inhibitors of the luteinizing hormone receptor. J Med Chem (2009) 52(7):2036–42.10.1021/jm801561h19296599
159. Heitman LH Oosterom J Bonger KM Timmers CM Wiegerinck PH Ijzerman AP. [3H]Org 43553, the first low-molecular-weight agonistic and allosteric radioligand for the human luteinizing hormone receptor. Mol Pharmacol (2008) 73(2):518–24.10.1124/mol.107.03987517989351
160. Davies TF Latif R. Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies. Expert Opin Ther Targets (2015) 19(6):835–47.10.1517/14728222.2015.101818125768836
161. Neumann S Raaka BM Gershengorn MC. Human TSH receptor ligands as pharmacological probes with potential clinical application. Expert Rev Endocrinol Metab (2009) 4(6):669.10.1586/eem.09.3620161662
162. Jaschke H Neumann S Moore S Thomas CJ Colson AO Costanzi S et al. A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). J Biol Chem (2006) 281(15):9841–4.10.1074/jbc.C60001420016488885
163. Neumann S Huang W Titus S Krause G Kleinau G Alberobello AT et al. Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice. Proc Natl Acad Sci U S A (2009) 106(30):12471–6.10.1073/pnas.090450610619592511
164. Neumann S Kleinau G Costanzi S Moore S Jiang JK Raaka BM et al. A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology (2008) 149(12):5945–50.10.1210/en.2008-083618669595
165. Neumann S Eliseeva E McCoy JG Napolitano G Giuliani C Monaco F et al. A new small-molecule antagonist inhibits Graves’ disease antibody activation of the TSH receptor. J Clin Endocrinol Metab (2011) 96(2):548–54.10.1210/jc.2010-193521123444
166. Turcu AF Kumar S Neumann S Coenen M Iyer S Chiriboga P et al. A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab (2013) 98(5):2153–9.10.1210/jc.2013-114923482611
167. van Koppen CJ de Gooyer ME Karstens WJ Plate R Conti PG van Achterberg TA et al. Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor. Br J Pharmacol (2012) 165(7):2314–24.10.1111/j.1476-5381.2011.01709.x22014107
168. van Zeijl CJ van Koppen CJ Surovtseva OV de Gooyer ME Plate R Conti P et al. Complete inhibition of rhTSH-, Graves’ disease IgG-, and M22-induced cAMP production in differentiated orbital fibroblasts by a low-molecular-weight TSHR antagonist. J Clin Endocrinol Metab (2012) 97(5):E781–5.10.1210/jc.2011-293122419705
169. Neumann S Nir EA Eliseeva E Huang W Marugan J Xiao J et al. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology (2014) 155(1):310–4.10.1210/en.2013-183524169564
170. Heitman LH Kleinau G Brussee J Krause G Ijzerman AP. Determination of different putative allosteric binding pockets at the lutropin receptor by using diverse drug-like low molecular weight ligands. Mol Cell Endocrinol (2012) 351(2):326–36.10.1016/j.mce.2012.01.01022269095
171. Schwartz TW Frimurer TM Holst B Rosenkilde MM Elling CE. Molecular mechanism of 7TM receptor activation – a global toggle switch model. Annu Rev Pharmacol Toxicol (2006) 46:481–519.10.1146/annurev.pharmtox.46.120604.14121816402913
172. Janovick JA Maya-Nunez G Ulloa-Aguirre A Huhtaniemi IT Dias JA Verbost P et al. Increased plasma membrane expression of human follicle-stimulating hormone receptor by a small molecule thienopyr(im)idine. Mol Cell Endocrinol (2009) 298(1–2):84–8.10.1016/j.mce.2008.09.01518848862