Prostaglandin receptors: Their role in regulating renal function

Current Opinion in Nephrology and Hypertension

Volumn 9, Issue 1, 2000, Pages 23-29

  Breyer, Matthew D ^a,b,c,d   Breyer, Richard M ^a,b,d  

^a Division of Nephrology   (United States)

^b Dept Molec Physiol and Biophys ^*  (United States)

^c VETERANS AFFAIRS MEDICAL CENTER   (United States)

^d VANDERBILT UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

11 DEOXY 16 PHENOXY 17,18,19,20 TETRANORPROSTAGLANDIN E1; 5 (6 CARBOXYHEXYL) 1 (3 CYCLOHEXYL 3 HYDROXYPROPYL)HYDANTOIN; 7 [5 (4 BIPHENYLYLMETHOXY) 2 MORPHOLINO 3 OXOCYCLOPENTYL] 4 HEPTENOIC ACID; ANGIOTENSIN; ARACHIDONIC ACID; COMPLEMENTARY DNA; CREATININE; CYCLIC AMP; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; GUANINE NUCLEOTIDE BINDING PROTEIN; INDOMETACIN; MESSENGER RNA; NONSTEROID ANTIINFLAMMATORY AGENT; POTASSIUM; PROSTACYCLIN; PROSTAGLANDIN RECEPTOR; RECEPTOR SUBTYPE; RENIN; SODIUM CHLORIDE; SULPROSTONE; THROMBOXANE RECEPTOR; WATER;

HUMAN; KIDNEY; KIDNEY FUNCTION; NONHUMAN; PRIORITY JOURNAL; REVIEW;

ANIMALS; HOMEOSTASIS; HUMANS; KIDNEY; MICE; RECEPTORS, PROSTAGLANDIN;

EID: 0033988783     PISSN: 10624821     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041552-200001000-00005     Document Type: Review

References (110)

1. 1 Bonvalet JP, Pradelles P, Farman N. Segmental synthesis and actions of prostaglandins along the nephron. Am J Physiol 1987; 253:F377-F387.
2. 2 Smith W. Prostanoid biosynthesis and mechanisms of action. Am J Physiol 1992; 263:F181-F191.
3. 3 Nowak J, Wennmalm A. Human forearm and kidney conversion of arachidonic acid to prostaglandins. Acta Physiol Scand 1979; 106:307-312.
4. 4 Coleman RA, Smith WL, Narumiya S. VIII. International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 1994; 46:205-229.
5. 5 Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev 1999; 79:1193-1226. This is a comprehensive and timely review of the molecular and systemic actions of all of the G-protein-coupled prostanoid receptors.
6. 6 Gurwitz J, Avorn J, Bohn R, Glynn R, Monane M, Mogun H. Initiation of antihypertensive treatment during nonsteroidal anti-inflammatory drug therapy. JAMA 1994; 272:781-786.
7. 7 Murray M, Breene P, Brater D, Manatunga A, Hall S. Effect of flurbiprofen on renal function in patients with moderate renal insufficiency. Br J Clin Pharmacol 1992; 33:385-393.
8. 8 Schlondorff D. Renal complications of nonsteroidal anti-inflammatory drugs. Kidney Int 1993; 44:643-653.
9. 9 Tan SY, Shapiro R, Franco R, Stockard H, Mulrow PJ. Indomethacin-induced prostaglandin inhibition with hyperkalemia. A reversible cause of hyporeninemic hypoaldosteronism. Ann Intern Med 1979; 90:783-785.
10. 10 Imanishi M, Kawamura M, Akabane S, Matsushima Y, Kuramochi M, Ito K, et al. Aspirin lowers blood pressure in patients with renovascular hypertension. Hypertension 1989; 14:461-468.
11. 11 Jackson E. Relationship between renin release and blood pressure response to nonsteroidal anti-inflammatory drugs in hypertension. Hypertension 1989; 14:469-471.
12. 2-induced hypertension in conscious dogs. Am J Physiol 1979; 237:H449-H454.
13. 13 Jensen B, Schmid C, Kurtz A. Prostaglandins stimulate renin secretion and renin mRNA in mouse renal juxtaglomerular cells. Am J Physiol 1996; 271:F659-669.
14. 14 Mistry M, Nasjletti A. Prostanoids as mediators of prohypertensive and antihypertensive mechanisms. Am J Med Sci 1988; 295:263-267.
15. 2 receptors: distinct subtypes mediate vascular smooth muscle contraction and platelet aggregation. J Pharmacol Exp Ther 1991; 258:74-81.
16. 2 receptor. Nature 1991; 349:617-620.
17. 2 receptor: cDNA cloning, expression and northern blot analysis. Biochem Biophys Res Commun 1992; 184:1197-1203.
18. 2 receptor: molecular cloning signal transduction and intrarenal expression localization. J Clin Invest 1995; 96:657-664.
19. 2 receptor alpha isoform (TP alpha) functionally couples to the G proteins Gq and G11 in vivo and is activated by the isoprostane 8-epi prostaglandin F2 alpha. J Pharmacol Exp Ther 1997; 281:957-964.
20. 20 Vezza R, Habib A, FitzGerald GA. Differential signaling by the thromboxane receptor isoforms via the novel GTP-binding protein, Gh. J Biol Chem 1999; 274:12774-12779.
21. 2 receptor. J Biol Chem. 1994; 269:19256-19261. (Published erratum appears in J Biol Chem 1995; 270:7011.)
22. 2 receptor. J Biol Chem. 1995; 270:7011.
23. 2 receptor gene. Biochem Biophys Res Commun 1999; 256:391-397.
24. 2 in the mouse kidney. Am J Physiol 1996; 271:F1131-F1138.
25. 2. J Clin Invest 1998; 102:1994-2001. A description is provided of the of the TP receptor knockout mouse physiology, focusing on the platelet defect and hemodynamic changes observed.
26. 26 Wilkes BM, Solomon J, Maita M, Mento PF. Characterization of glomerular thromboxane receptor sites in the rat. Am J Physiol 1989; 256:F1111-F1116.
27. 27 Spurney RF, Onorato JJ, Albers FJ, Coffman TM. Thromoboxane binding and signal transduction in rat glomerular mesangial cells. Am J Physiol 1993; 264:F292-F299.
28. 2 receptor in a dominantly inherited bleeding disorder. J Clin Invest 1994; 94:1662-1667.
29. 29 Spurney RF, Ruiz P, Pisetsky DS, Coffman TM. Chronic thromboxane receptor blockade reduces renal injury in murine lupus nephritis. Kidney Int 1992; 41:973-982.
30. 30 DeRubertis FR, Craven PA. Activation of protein kinase C in glomerular cells in diabetes: mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 1994; 43:1-8.
31. 31 Abramovitz M, Boie Y, Nguyen T, Rushmore TH, Bayne MA, Metters KM, et al. Cloning and expression of a cDNA for the human prostanoid FP receptor. J Biol Chem 1994; 269:2632-2636.
32. 32 Kiriyama M, Ushikubi F, Kobayashi T, Hirata M, Sugimoto Y, Narumiya S. Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. Br J Pharmacol 1997; 122:217-224.
33. 33 Sugimoto Y, Hasumoto K, Namba T, Irie A, Katsuyama M, Negishi M, Kakizuka A, Naumiya S, Ichikawa A. Cloning and expression of a cDNA for mouse prostaglandin F receptor. J Biol Chem 1994; 269:1356-1360.
34. 34 Sugimoto Y, Yamasaki A, Segi E, Tsuboi K, Aze Y, Nishumra T, et al. Failure of parturition in mice lacking the prostagtandin F receptor. Science 1997; 277:681-683.
35. 35 Hasumoto K, Sugimoto Y, Gotoh M, Segi E, Yamasaki A, Yamaguchi M, et al. Characterization of the mouse prostaglandin F receptor gene: a transgenic mouse study of a regulatory region that controls its expression in the stomach and kidney but not in the ovary. Genes Cells 1997; 2:571-580.
36. 36 Stokes JB. Modulation of vasopressin-induced water permeability of the cortical collecting tubule by endogenous and exogenous prostaglandins. Miner Electrolyte Metab 1985; 11:240-248.
37. 2 receptors modulate water and sodium transport in rabbit cortical collecting duct. Am J Physiol 1993; 265:F643-F650.
38. 38 Funk C, Furchi L, FitzGerald G, Grygorczyk R, Rochette C, Bayne MA, et al. Cloning and expression of a cDNA for the human prostaglandin E receptor EP1 subtype. J Biol Chem 1993; 268:26767-26772.
39. 39 Breyer MD, Jacobson HR, Davis LS, Breyer RM. In situ hybridization and localization of mRNA for the rabbit prostaglandin EP3 receptor. Kidney Int 1993; 43:1372-1378.
40. 40 Boie Y, Stocco R, Sawyer N, Slipetz DM, Ungrin MD, Neuschafer-Rube F, et al. Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes. Eur J Pharmacol 1997; 340:227-241.
41. 41 Schaefer M, Hofmann T, Schultz G, Gudermann T. A new prostaglandin E receptor mediates calcium influx and acrosome reaction in human spermatozoa. Proc Natl Acad Sci USA 1998; 95:3008-3013.
42. 42 Toh H, Ichikawa A, Narumiya S. Molecular evolution of receptors for eicosanoids. FEBS Lett 1995; 361:17-21.
43. 43 Sugimoto Y, Namba T, Shigemoto R, Negishi M, Ichikawa A, Narumiya S. Distinct cellular localization of mRNAs for three subtypes of prostaglandin E receptor in kidney. Am J Physiol 1994; 266:F823-828.
44. 2 receptor mRNA along mouse nephron segments by RT-PCR. Am J Physiol 1994. 266:C1453-1458.
45. 4 receptor. Am J Physiol 1996; 270:F485-F493.
46. 46 Breyer M, Davis L, Jacobson H, Breyer R. Differential localization of prostaglandin E receptor subtypes in human kidney. Am J Physiol 1996; 270:F912-F918.
47. 1 subtype of prostaglandin E receptor. J Biol Chem 1993; 268:20175-20178.
48. 1 receptor gene. Eur J Biochem 1995; 231:809-814.
49. 2 antagonist and analgesic. Bioorg Med Chem Lett 1994; 4:509-514.
50. 50 Hallinan E, Hagen T, Jusa R, Tsymbalov S, Rao S, vanHoeck J-P, et al. N-substituted dibenzoxazepines as analgesic PGE2 antagonists. J Med Chem 1993; 36:3293-3299.
51. 1 receptor antagonist blocks the diarrheagenic, but not cytoprotective, actions of a synthetic prostaglandin. Drug Dev Res 1995; 34:35-38.
52. 1 subtype. J Biol Chem 1996; 271:31255-31261.
53. 53 Abramovitz M, Adam M, Boie Y, Grygorczyk R, Rushmore T, Nguyen T, et al. Human prostanoid receptors: cloning and characterzation. Adv Prostagl Thrombox Leukotr Res 1995; 23:499-504.
54. 2.
55. 1 prostanoid receptor and the PKN protein kinase overlap. Biochem Biophys Res Commun 1996; 227:70-76.
56. 2 inhibits sodium transport in the rabbit CCD by raising intracellular calcium. J Clin Invest 1991; 87:1992-1998.
57. 57 Ishibashi R, Tanaka I, Kotani M, Mura S, Goto M, Sugawara A, et al. Roles of prostaglandin E receptors in mesangial cells under high-glucose conditions. Kidney Int 1999; 56:589-600.
58. 2 EP1 receptor subtype have hypotension, hyperreninemia and altered responses to angiotensin II [abstract]. FASEB J 1999; 13:A1549.
59. 59 Nishigaki N, Negishi M, Honda A, Sugimoto Y, Namba T, Narumiya S, Ichikawa A. Identification of prostaglandin E receptor 'EP2 cloned from mastocytoma cells as EP4 subtype. FEBS Lett 1995; 364:339-341.
60. 60 Guan Y, Breyer R, Zhang Y-H, Davis L, Redha R, Nian C, Jacobson H, Breyer M. Cloning and functional expression of the Rabbit prostaglandin EP2 receptor [abstract], J Am Soc Nephrol 1996; 7:1646.
61. 61 Katsuyama M, Nishigaki N, Sugimoto Y, Morimoto K, Negishi M, Narumiya S, Ichikawa A. The mouse prostaglandin E receptor EP2 subtype: cloning, expression, and northern blot analysis. FEBS Lett 1995; 372:151-156.
62. 62 Regan JW, Bailey TJ, Pepperl DJ, Pierce KL, Bogardus AM, Donello JE, et al. Cloning of a novel human prostaglandin receptor with characteristics of the pharmacologically defined EP2 subtype. Mol Pharmacol 1994; 46:213-220.
63. 63 Nemoto K, Pilbeam CC, Bilak S, Raisz L. Molecular cloning and expression of the rat prostaglandin E2 receptor of the EP2 Subtype. Prostaglandins 1997; 54:713-725.
64. 2 subtype. J Biol Chem 1994; 269:11873-11877.
65. 65 Coleman RA, Grix SP, Head SA, Louttit JB, Mallett A, Sheldrick RLG. A novel inhibitory prostanoid receptor in piglet saphenous vein. Prostaglandins 1994; 47:151-168.
66. 66 Hizaki H, Segi E, Sugimoto Y, Hirose M, Saji T, Ushikubi F, et al. Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP(2). Proc Natl Acad Sci USA 1999; 96:10501-10506.
67. 67 Lim H, Dey SK. Prostaglandin E2 receptor subtype EP2 gene expression in the mouse uterus coincides with differentiation of the luminal epithelium for implantation. Endocrinology 1997; 138:4599-4606.
68. 68 Kennedy C, Zhang Y, Brandon S, Guan S, Coffee K, Funk C, et al. Hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nature Med 1999; 5:217-220. Evidence is provided that the EP2 receptor plays a role regulating blood pressure and fertility.
69. 69 Tilley SL, Audoly LP, Hicks EH, Kim HS, Flannery PJ, Coffman TM, Koller BH. Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor. J Clin Invest 1999; 103:1539-1545. Evidence is provided that the EP2 receptor plays a role regulating blood pressure and fertility.
70. 70 Schmid A, T KH, S WD, D H. Splice variants of the human EP3 receptor for prostaglandin E2. Eur J Biochem 1995; 15:23-30.
71. 71 Namba T, Sugimoto Y, Negishi M, Irie A, Ushikubi F, Kakizuka A, et al. Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity. Nature 1993; 365:166-170.
72. 72 Irie A, Sugimoto Y, Namba T, Harazono A, Honda A, Watabe A, et al. Third isoform of the prostaglandin-E-receptor EP3 subtype with different C-terminal tail coupling to both stimulation and inhibition of adenylate cyclase. Eur J Biochem 1993; 217:313-318.
73. 73 An S, Yang J, So S, Zeng L, Goetzl E. Isoforms of the EP3 subtype of human prostaglandin E2 receptor transduce both intracellular calcium and cAMP signals. Biochemistry 1994; 33:14496-14502.
74. 74 Breyer RM, Emeson RB, Breyer MD, Abromson RM, Davis LS, Ferrenbach SM. Alternative splicing generates multiple isoforms of a rabbit prostaglandin E2 receptor. J Biol Chem 1994; 298:6163-6169.
75. 75 Regan JW, Bailey TJ, Donello JE, Pierce KL, Pepperl DJ, Zhang D, et al. Molecular cloning and expression of human EP3 receptors: evidence for three variants with different termini. Br J Pharmacol 1994; 112:6163-6169.
76. 76 Aoki J, Katoh H, Yasui H, Yamaguchi Y, Nakamura K, Hasegawa H, et al. Signal transduction pathway regulating prostaglandin EP3 receptor-induced neurite retraction: requirement for two different tyrosine kinases. Biochem J 1999; 340:365-369.
77. 77 Audoly L, Ma L, Feoktistov I, Breyer M, Breyer R. EP3 receptor activation of cAMP response element mediated gene transcription. J Pharmacol Exp Ther 1999; 289:140-148.
78. 78 Hasegawa H, Negishi M, Ichikawa A. Two isoforms of the prostaglandin E receptor EP3 subtype different in agonist-independent constitutive activity. J Biol Chem 1996; 271:1857-1860.
79. 2. Biochem Biophys Res Commun 1994; 198:999-1006.
80. 80 Ushikubi F, Segi E, Sugimoto Y, Murata T, Matsuoka T, Kobayashi T, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 1998; 395:281-284. A description of all the EP receptor knockout mice is provided, and evidence is given that the EP3 receptor in particular is responsible for the generation of fever, and therefore blocking its activation may account for the antipyretic effects of nonsteroidal anti-inflammatory drugs and aspirin.
81. 81 Fleming E, Athirakul K, Oliverio M, Key M, Goulet J, Koller B, Coffman T. Urinary concentrating function in mice lacking the EP3 receptors for prostaglandin E2. Am J Physiol 1998; 275:F955-961. Characterization of the renal phenotype of EP3 knockout mice is provided.
82. 82 Sugimoto Y, Namba T, Negishi M, Ichikawa A, Narumiya S. Cloning and expression of a cDNA for mouse prostaglandin E receptor EP3 subtype. J Biol Chem 1992; 267:6463-6466.
83. 83 An S, Yang J, Xia M, Goetzl EJ. Cloning and expression of the EP2 subtype of human receptors for prostaglandin E2. Biochem Biophys Res Commun 1993; 197:263-270.
84. 84 Honda A, Sugimoto Y, Namba T, Watanbe A, Irie A, Negishi M, et al. Cloning and expression of a cDNA for mouse prostaglandin E receptor EP2 subtype. J Biol Chem 1993; 268:7759-7762.
85. 85 Sando T, Usui T, Tanaka I, Mori K, Sasaki Y, Fukuda Y, et al. Molecular cloning and expression of rat prostaglandin E receptor EP2 subtype. Biochem Biophys Res Commun 1994; 200:1329-1333.
86. 86 Segi E, Sugimoto Y, Yamasaki A, Aze Y, Oida H, Nishimura T, et al. Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice. Biochem Biophys Res Commun 1998; 246:7-12. Evidence is provided that the EP4 receptor plays an important role in closure of the ductus arteriosus.
87. 87 Nguyen M, Camenisch T, Snouwaert J, Hicks E, Coffman T, Anderson P, Malouf N, Koller B. The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth. Nature 1997; 390-78-81.
88. 88 Audoly L, Goulet J, Key M, Nguyen M, Koller B, Coffman T. EP4 but not EP3 receptors mediate vasodilatory actions of PGE2 [abstract]. J Am Soc Nephrol 1998; 9:333.
89. 89 Csukas S, Hanke C, Rewolinski D, Campbell W. Prostaglandin E2-induced aldosterone release is mediated by an EP2 receptor. Hypertension 1998; 31:575-581.
90. 90 Jensen BL, Mann B, Skott O, Kurtz A. Differential regulation of renal prostaglandin receptor mRNAs by dietary salt intake in the rat. Kidney Int 1999; 56:528-537. This is an interesting study suggesting the EP4 receptor may be important for the effects of salt on renin release.
91. 91 Namba T, Oida H, Sugimoto Y, Kakizuka A, Negishi M, Ichikawa A, Narumiya S. cDNA cloning of a mouse prostacyclin receptor: multiple signaling pathways and expression in thymic medulla. J Biol Chem 1994; 269:9986-9992.
92. 92 Boie Y, Rushmore TH, Darmon-Goodwin A, Grygorczyk R, Slipetz DM, Metters KM, Abramovitz M. Cloning and expression of a cDNA for the human prostanoid IP receptor. J Biol Chem 1994; 269:12173-12178.
93. 93 Oida H, Namba T, Sugimoto Y, Ushikubi F, Ohishi H, Ichikawa A, Narumiya S. In situ hybridization studies on prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol 1995; 116:2828-2837.
94. 94 Oida H, Namba T, Sugimoto Y, Ushikubi F, Ohishi H, Ichikawa A, Narumiya S. In situ hybridization studies on prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol 1995; 116:2828-2837.
95. 95 Murata T, Ushikubi F, Matsuoka T, Hirata M, Yamasaki A, Sugimoto Y, et al. Altered pain perception and inflammatory response in mice lacking prostacyclin recpetor. Nature 1997; 388:678-682.
96. 96 Bolger PM, Einser GM, Ramwell PW, Slotkoff LM, Corey EJ. Renal action of prostacyclin. Nature 1978; 271:467-469.
97. 97 Edwards RM. Effects of prostaglandins on vasoconstrictor action in isolated renal arterioles. Am J Physiol 1985; 248:F779-F784.
98. 98 Bugge JF, Stokke ES, Vikse A, Kiil F. Stimulation of renin release by PGE2 and PGI2 infusion in the dog: enhancing effect of ureteral occlusion or administration of ethacrynic acid. Acta Physiol Scand. 1990; 138:193-201.
99. 99 Ito S, Carretero OA, Abe K, Beierwaltes WH, Yoshinaga K. Effect of prostanoids on renin release from rabbit afferent arterioles with and without macula densa. Kidney Int 1989; 35:1138-1144.
100. 100 Chaudhari A, Gupta S, Kirschenbaum M. Biochemical evidence for PGI2 and PGE2 receptors in the rabbit renal preglomerular microvasculature. Biochim Biophys Acta 1990; 1053:156-161.
101. 101 Yahata K, Tanaka I, Mukoyama M, Kasahara M, Ishibashi R, Kotani M, et al. Blood pressure, renal function, salt handling and renin release in prostacyclin receptor knockout mice [abstract]. J Am Soc Nephrol 1998; 9:417A.
102. 102 Hebert RL, O'Connor T, Neville C, Burns KD, Laneuville O, Peterson LN. Prostanoid signaling, localization, and expression of IP receptors in rat thick ascending limb cells. Am J Physiol 1998; 275:F904-F914.
103. 103 Komhoff M, Lesener B, Nakao K, Seyberth HW, Nusing RM. Localization of the prostacyclin receptor in human kidney. Kidney Int 1998; 54:1899-1908.
104. 104 Veis JH, Dillingham MA, Berl T. Effects of prostacyclin on the cAMP system in cultured rat inner medullary collecting duct cells. Am J Physiol 1990; 258:F1218-F1223.
105. 105 Lewis RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ. Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J Immunol 1982; 129:1627-1631.
106. 106 Hirata M, Kakuzuka A, Aizawa M, Ushikubi F, Narumiya S. Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene. Proc Natl Acad Sci USA 1994; 91:11192-11196.
107. 107 Boie Y, Sawyer N, Slipetz D, Metters K, Abramovitz M. Molecular cloning and characterization of the Human Prostanoid DP receptor. J Biol Chem 1995; 270:18910-18916.
108. 108 Oida H, Hirata M, Sugimoto Y, Ushikubi F, Ohishi H, Mizuno N, et al. Expression of messenger RNA for the prostaglandin D receptor in the leptomeninges of the mouse brain. FEBS Lett 1997; 417:53-56.
109. 109 Rao PS, Cavanagh D, Dietz JR, Marsden K, O'Brien WF, Spaziani E. Dose-dependent effects of prostaglandin D2 on hemodynamics renal function, and blood gas analyses. Am J Obstet Gynecol 1987; 156:843-851.
110. 110 Left P, Giles H. Classification of platelet and vascular prostaglandin D2 (DP) receptors: estimation of affinities and relative efficacies for a series of novel bicyclic ligands. Br J Pharmacol 1992; 106:996-1003.