Abstract
Reports in 1990 on some weakly to moderately active nonpeptides which were not originally designed for neuropeptide Y (NPY) receptors, followed by the discovery of the first highly potent and selective Y1 receptor antagonists— the (R)-argininamide BIBP 3226 and the benzamidine derivative SR 120819A—as well as raising hope for novel drug treatment of hypertension, obesity and metabolic diseases stimulated the search for NPY-blocking compounds. Most of the currently known nonpeptidic NPY antagonists are ligands of Y1 or Y5 receptors, whereas only one class of Y2 selective antagonists around the (S)-arginine derivative BIIE 0246 has been disclosed. Nonpeptidic ligands of the Y Y4 receptor are not known. In some cases the design of Y1 antagonists followed rational strategies considering amino acids which are essential for binding to Y1 and/or Y2 receptors according to results of a complete alanine scan of NPY. Typical Y1 antagonists (e.g., compounds of the argininamide, benzamidine, benzimidazole, indole and aminopyridine series) have one or two basic groups which—according to the working hypothesis—could mimic Arg33 and/ or Arg35 in NPY. Binding models derived for some compounds (e.g., BIBP 3226 and J-104870) based on investigations with Y1 receptor mutants suggest key interactions between the basic group(s) and acidic residues of the Y1 receptor protein, especially Asp287. Compared to Y1 antagonists the known Y5 antagonists are often based on hits from screening of libraries and show a considerably higher degree of structural diversity. Nevertheless many highly active Y5 antagonists represent a common structural pattern suggesting at least overlapping binding sites.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Abounader R, Villemure JG, Hamel E (1995) Characterization of neuropeptide Y (NPY) receptors in human cerebral arteries with selective agonists and the new Y1 antagonist BIBP 3226. Br J Pharmacol 116:2245–2250
Aiglstorfer I, Uffrecht A, Gessele K et al. (1998) NPY Y1 antagonists: structure-activity relationships of arginine derivatives and hybrid compounds with arpromidine-like partial structures. Regul Pept 75/76:9–21
Aiglstorfer I, Hendrich I, Moser C et al. (2000) Structure-activity relationships of neuropeptide Y Y1 receptor antagonists related to BIBP 3226. Bioorg Med Chem Lett 10:1597–1600
Akwabi-Ameyaw A, Heyer D, Aquino C et al. (2001) Synthesis and SAR of substituted 5-acylamino benzimidazoles as potent neuropeptide Y Y5 antagonists. 222nd ACS National Meeting. Chicago, August 2001 (abstract MEDI-033)
Allen J, Novotny J, Martin J et al. (1987) Molecular structure of mammalian neuropeptide Y: analysis by molecular cloning and computer-aided comparison with crystal structure of avian homologue. Proc Natl Acad Sci USA 84:2532–2536
Antonsson T, Bergman N-A, Linschoten M et al., AstraZeneca (2001) Preparation and effect of diphenylacetylaminoalkylamides as neuropeptide Y antagonists. Patent WO 2001002364
Aoki K, Nishikawa N, Ikekawa A et al., Meiji Seika Kaisha, Japan (2001) Preparation of benzothiazolone derivatives having affinity to neuropeptide Y receptor. Patent Jp 2001122865
Beck-Sickinger AG, Wieland HA, Wittneben H et al. (1994) Complete L-alanine scan of neuropeptide Y reveals ligands binding to Y1 and Y2 receptors with distinguished conformations. Eur J Biochem 225:947–958
Beck-Sickinger AG (1997) The importance of various parts of the NPY molecule for receptor recognition. In: Grundemar L, Bloom SR (eds) Neuropeptide Y and drug development. Academic Press, London, San Diego, pp 107–126
Bell D, McDermott BJ (1998) D-myo inositol 1,2,6, trisphosphate (α-trinositol, pp56): selective antagonist at neuropeptide Y (NPY) Y-receptors or selective inhibitor of phosphatidylinositol cell signaling? Gen Pharmacol 31:689–696
Benfey BG (1982) Two long acting alpha-adrenoceptor blocking drugs: benextramine and phenoxybenzamide. Trends Pharmacol Sci 8:231
Berglund MM, Fredriksson R, Salaneck E et al. (2002) Reciprocal mutations of neuropeptide Y receptor Y2 in human and chicken identify amino acids important for antagonist binding. FEBS Lett 518:5–9
Block MH, Donald CS, Foote KM et al, AstraZeneca UK Ltd (2001) Preparation of carbazoles as neuropeptide Y5 receptor ligand. Patent WO 0107409
Block MH, Boyer S, Brailsford W et al. (2002) Discovery and optimization of a series of carbazole ureas as NPY5 antagonists for the treatment of obesity. J Med Chem 45:3509–3523
Blum CA, Desimone R, Hutchison A et al., Neurogen Corp., USA (2000) Certain amidoand amino-substituted benzylamine derivatives; a new class of neuropeptide Y1 specific ligands. Patent US 6133265
Britton TC, Spinazze PG, Hipskind PA et al. (1999) Structure-activity relationships of a series of benzothiophene-derived NPY Y1 antagonists: optimization of the C-2 side chain. Bioorg Med Chem Lett 9:475–480
Buschauer A (1989) Synthesis and in vitro pharmacology of arpromidine and related phenyl( pyridylalkyl)guanidines, a potential new class of positive inotropic drugs. J Med Chem 32:1963–1970
Carpino PA, Hammond M, Hank RF, Pfizer Products Inc., USA (2000) Amide derivatives useful as Neuropeptide Y (NPY) antagonists. Patent EP 1033366
Carpino PA (2000) Patent focus on new anti-obesity agents: September 1999–February 2000. Expert Opin Ther Pat 10:819–831
Chaurasia C, Misse G, Tessel R et al. (1994) Nonpeptide peptidomimetic antagonists of the neuropeptide Y receptor: benextramine analogs with selectivity for the peripheral Y2 receptor. J Med Chem 37:2242–2248
Connell RD, Lease TG, Ladouceur GH et al., Bayer Corp., USA (2000) Amide derivatives and methods for using the same as selective neuropeptide Y receptor antagonists. Patent US 6048900
Criscione L, Yamaguchi Y, Mah R et al., Novartis AG, Switzerland (1997) Receptor Antagonists. Patent WO 9720823
Criscione L, Rigollier P, Batzl-Hartmann C et al. (1998) Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor. J Clin Invest 102:2136–2145
Daniels AJ, Chance WT, Grizzle MK et al. (2001) Food intake inhibition and reduction in body weight gain in rats treated with GI264879A, a non-selective NPY-Y1 receptor antagonist. Peptides 22:483–491
Daniels AJ, Grizzle MK, Wiard RP et al. (2002) Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist. Regul Pept 106:47–54
Dax SL, Lovenberg TW, Baxter EW et al., Ortho-McNeil (2000) N-Aralkylaminotetralins as ligands for the neuropeptide Y Y5 receptor. Patent WO 0020376
Dax SL, McNally JJ, Ortho-McNeil (2000) 3a,4,5,9b-tetrahydro-lH-benz[e]indol-2-yl amine-derived neuropeptide Y receptor ligands useful in the treatment of obesity and other disorders. Patent WO 0068197
Dax SL, McNally JJ, Youngman MA, Ortho-McNeil (2001) Amine and amide derivatives as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders. Patent WO 0109120
Dax SL (2002) Small-molecule neuropeptide Y Y5 antagonists. Drugs Fut 27:273–287
Delia Zuana O, Sadlo M, Germain M et al. (2001) Reduced food intake in response to CGP 71683A may be due to mechanisms other than NPY Y5 receptor blockade. Int J Obes Relat Metab Disord 25:84–94
Dollinger H, Esser F, Mihm G et al., Boehringer Ingelheim Pharma K.-G., Germany (1999) Preparation of novel peptides for use as NPY antagonists. Patent DE 19816929
Donald CS, Foote KM, Schofield P et al., AstraZeneca, UK (2002) Carbazole derivatives and their use as neuropeptide Y5 receptor ligands. Patent WO 02051806
Doods H, Gaida W, Wieland HA et al. (1999) BIIE0246: A selective and high affinity neuropeptide Y Y2 receptor antagonist. Eur J Pharmacol 384:R3–R5
Doods HN, Wienen W, Entzeroth M et al. (1995) Pharmacological characterization of the selective nonpeptide neuropeptide Y1 receptor antagonist BIBP 3226. J Pharmacol ExpTher 275:136–142
Doods HN, Wieland HA, Engel W et al. (1996) BIBP 3226, the first selective neuropeptide Y1 receptor antagonist: a review of its pharmacological properties. Regul Pept 65:71–77
Doughty MB, Chu SS, Miller DW et al. (1990) Benextramine: a long-lasting neuropeptide Y receptor antagonist. Eur J Pharmacol 185:113–114
Doughty MB, Li K, Hu L et al. (1992) Benextramine-neuropeptide Y (NPY) binding site interactions: characterization of 3H-NPY binding site heterogeneity in rat brain. Neuropeptides (Edinburgh) 23:169–180
Doughty MB, Chaurasia CS, Li K (1993) Benextramine-neuropeptide Y receptor interactions: contribution of the benzylic moieties to [3H]neuropeptide Y displacement activity. J Med Chem 36:272–279
Dove S, Michel MC, Knieps S et al. (2000) Pharmacology and quantitative structure-activity relationships of imidazolylpropylguanidines with mepyramine-like substructures as non-peptide neuropeptide Y Y1 receptor antagonists. Can J Physiol Pharmacol 78:108–115
Dow RL, Hammond M, Pfizer Products Inc., USA (2001) 4-aminopyrrolo[3,2-d]pyrimidines as neuropeptide Y receptor antagonists. Patent US 6187778
Du P, Salon JA, Tamm JA et al. (1997a) Modeling the G-protein-coupled neuropeptide Y Y1 receptor agonist and antagonist binding sites. Protein Eng 10:109–117
Du P, Finn JM, Jeon YT et al., Synaptic Pharmaceutical Corp. (1997b) Aryl sulfonamide and sulfamide derivatives and uses thereof. Patent WO 9719682
Duhault J, Boulanger M, Chamorro S et al. (2000) Food intake regulation in rodents: Y5 or Y1 NPY receptors or both? Can J Physiol Pharmacol 78:173–185
Dumont Y, Cadieux A, Doods H et al. (2000a) BIIE0246, a potent and highly selective non-peptide neuropeptide Y Y2 receptor antagonist. Br J Pharmacol 129:1075–1088
Dumont Y, Cadieux A, Doods H et al. (2000b) Potent and selective tools to investigate neuropeptide Y receptors in the central and peripheral nervous systems: BIBO3304 (Y1) and CGP71683A (Y5). Can J Physiol Pharmacol 78:116–125
Edvinsson L, Adamsson M, Jansen I (1990) Neuropeptide Y antagonistic properties of D-myo-inositol-1.2.6-trisphosphate in guinea pig basilar arteries. Neuropeptides 17:99–105
Elliott RL, Hammond M, Hank RF, Pfizer Products Inc. (2000) 2-Pyridyl-4-heteroarylimidazoles for the treatment of obesity. Patent WO 0066578
Elliott RL, Oliver RM, Hammond M et al. (2003) In vitro and in vivo characterization of 3-[2-[6-(2-tert-butoxyethoxy)pyridin-3-yl]-lH-imidazol-4-yl]benzonitrile hydrochloride salt, a potent and selective NP Y5 receptor antagonist. J Med Chem 46:670–673
Esser F, Schnorrenberg G, Dollinger H et al., Boehringer Ingelheim Pharma K.-G., Germany (1999) Preparation of novel peptides for use as NPY antagonists. Patent DE 19816932
Fang J, Aquino C, Heyer D et al. (2001) 2-Aminobenzimidazoles as neuropeptide Y Y5 antagonists: Solution phase synthesis and structure-activity relationships. 222nd ACS National Meeting. Chicago, August 2001 (abstractMEDI-026)
Fauchere J-L, Ortuno J-C, Duhault J et al., Adir et Compagnie, France (2000) Aminotriazole compounds useful as neuropeptide Y receptor ligands, process for their preparation, and pharmaceutical compositions containing them. Patent EP 1044970
Feletou M, Rodriguez M, Beauverger P et al. (1998) NPY receptor subtypes involved in the contraction of the proximal colon of the rat. Regul Pept 75/76:221-229
Feletou M, Nicolas JP, Rodriguez M et al. (1999) NPY receptor subtype in the rabbit isolated ileum. Br J Pharmacol 127:795–801
Feth F, Erdbrugger W, Rascher W et al. (1993) Is PP56 (D-myo-inositol-l,2,6-trisphosphate) an antagonist at neuropeptide Y receptors? Life Sci 52:1835–1844
Fotsch C, Sonnenberg JD, Chen N et al. (2001) Synthesis and structure-activity relationships of trisubstituted phenyl urea derivatives as neuropeptide Y5 receptor antagonists. J Med Chem 44:2344–2356
Fritz JE, Kaldor SW, Scott WL et al, Eli Lilly & Co. (1998) 3-Arylpropylamino Neuropeptide Y Receptor Antagonists. Patent WO 9852890
Fukami T, Fukuroda T, Kanatani A et al., Banyu Pharm. (1998a) Preparation of urea moiety-containing pyrazole derivatives as neuropeptide Y antagonists. Patent WO 9824768
Fukami T, Fukuroda T, Kanatani A et al., Banyu Pharm. (1998b) Preparation of pyrazole derivatives for treatment of bulimia, obesity, and diabetes. Patent WO 9825907
Fukami T, Fukuroda T, Kanatani A et al., Banyu Pharm. (1998c) Preparation of aminopyrazole derivatives for the treatment of bulimia, obesity, and diabetes. Patent WO 9827063
Fukami T, Fukuroda T, Kanatani A et al., Banyu Pharm. (1998d) Preparation of novel aminopyrazole derivatives as neuropeptide Y antagonists. Patent WO 9825908
Fukami T, Okamoto O, Fukuroda T et al., Banyu Pharm. (1998e) Preparation and formulation of aminopyridine derivatives as neuropeptide Y receptor antagonists. Patent WO 9840356
Fukami T, Kanatani A, Ishihara A et al. (2001a) Synthesis and pharmacology of potent and selective aminopyridine NPY Y1 receptor antagonists. 222nd ACS National Meeting. Chicago, August 2001 (abstract MEDI-282)
Fukami T, Kanatani A, Ishihara A et al., Banyu Pharm. (2001b) Preparation of spiroisoindolinepiperidines, spiroisoquinolinepiperidines, spiroisobenzofuranpiperidines and related compounds. Patent WO 0114376
Fukuroda T, Kanatani A, Fukami T et al., Banyu Pharmaceutical Co. Ltd. (2001) Novel neuropeptide Y receptor antagonists. Patent WO 9915516
Gao Y, McNeil D, Yang L et al., Merck; Banyu Pharm. (2000) Preparation of spiroindolines as Y5 receptor antagonists. Patent WO 0027845
Gerald C, Walker MW, Criscione L et al. (1996) A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 382:168–171
Gerald C, Weinschank RL, Walker MW et al, Synaptic Pharma Corp. (USA) (1997) DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) and uses thereof. Patent WO 9616542
Grouzmann E, Buclin T, Martire M et al. (1997) Characterization of a selective antagonist of neuropeptide Y at the Y2 receptor. Synthesis and pharmacological evaluation of a Y2 antagonist. J Biol Chem 272:7699–7706
Grundemar L, Bloom SR (eds) (1997) Neuropeptide Y and drug development. London, San Diego, Academic Press
Hammond M (2001) Neuropeptide Y receptor antagonists. IDrugs 4:920–927
Heilig M, Edvinsson L, Wahlestedt C (1991) Effects of intracerebroventricular D-myoinositol-l,2,6-trisphosphate (PP56), a proposed neuropeptide Y (NPY) antagonist, on locomotor activity, food intake, central effects of NPY and NPY-receptor binding. Eur J Pharmacol 209:27–32
Heyer D, Marron B, Miyasaki Y et al. (2001a) Discovery of a novel series of benzimidazole-based neuropeptide Y Y5 antagonists from a 7-TM targeted chemical library. 222nd ACS National Meeting, Chicago, August 2001 (abstract MEDI-030)
Heyer D, Akwabi-Ameyaw A, Aquino C (2001b) Aminobenzimidazoles: A class of orally bioavailable and brain permeable neuropeptide Y Y5 antagonists. 222nd ACS National Meeting, Chicago, August 2001: (abstract MEDI-284)
Hipskind PA, Lobb KL, Nixon JA et al. (1997) Potent and selective 1,2,3-trisubstituted indole NPY Y-1 antagonists. J Med Chem 40:3712–3714
Hutzler C (2001) Synthesis and pharmacological activity of new neuropeptide Y receptor ligands: from N,N-disubstituted alkanamides to highly potent argininamide-type Y1 antagonists. Doctoral thesis, University of Regensburg, Regensburg, Germany
Hutzler C, Kracht J, Mayer M et al. (2001) NG-Acylated argininamides: highly potent selective NPY Y1 receptor antagonists with special properties, Arch. Pharm. Pharm. Med. Chem. 334,Suppl. 2, 17 (2001)
Islam I, Dhanoa D, Finn J et al. (2002) Discovery of potent and selective small molecule NPY Y5 receptor antagonists. Bioorg Med Chem Lett 12:1767–1769
Itani H, Ito H, Sakata Y et al. (2002a) Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3:7-methoxy-l-hydroxy-1-substituted tetraline derivatives. Bioorg Med Chem Lett 12:799–802
Itani H, Ito H, Sakata Y et al. (2002b) Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 2: substituted benzo[a]cycloheptene derivatives. Bioorg Med Chem Lett 12:757–761
Iyengar S, Li DL, Simmons RM (1999) Characterization of neuropeptide Y-induced feeding in mice: do Y1–Y6 receptor subtypes mediate feeding? J Pharmacol Exp Ther 289:1031–1040
Jacques D, Cadieux A, Dumont Y et al. (1995) Apparent affinity and potency of BIBP3226, a non-peptide neuropeptide Y receptor antagonist, on purported neuropeptide Y Y1, Y2 and Y3 receptors. Eur J Pharmacol 278:R3–5
Kanatani A, Kanno T, Ishihara A et al. (1999) The novel neuropeptide Y Y1 receptor antagonist J-104870: a potent feeding suppressant with oral bioavailability. Biochem Biophys Res Commun 266:88–91
Kanatani A, Ishihara A, Iwaasa H et al. (2000a) L-152,804: orally active and selective neuropeptide Y Y5 receptor antagonist. Biochem Biophys Res Commun 272:169–173
Kanatani A, Mashiko S, Murai N et al. (2000b) Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice. Endocrinology 141:1011–1016
Kanatani A, Hata M, Mashiko S et al. (2001) A typical Y1 receptor regulates feeding behaviors: effects of a potent and selective Y1 antagonist, J-115814. Mol Pharmacol 59:501–505
Kanno T, Kanatani A, Keen SLC et al. (2001) Different binding sites for the neuropeptide Y Y1 antagonists 1229U91 and J-104870 on human Y1 receptors. Peptides 22:405–413
Kask A, Rago L, Harro J (1998) Evidence for involvement of neuropeptide Y receptors in the regulation of food intake: studies with Y1-selective antagonist BIBP3226. Br J Pharmacol 124:1507–1515
Kask A, Harro J (2000) Inhibition of amphetamine-and apomorphine-induced behavioural effects by neuropeptide Y Y(1) receptor antagonist BIBO 3304. Neuropharmacology 39:1292–1302
Kask A, Vasar E, Heidmets LT et al. (2001) Neuropeptide Y Y(5) receptor antagonist CGP71683A: the effects on food intake and anxiety-related behavior in the rat. Eur J Pharmacol 414:215–224
Kawanishi Y, Takenaka H, Hanasaki K et al., Shionogi + Co., Ltd, Japan (2001) Preparation of sulfonamides and sulfinamides as NPY Y5 antagonists. Patent WO 0137826
Kirkpatrick P (2002) Dead end for NPY Y5-receptor antagonists? Nature Rev Drug Discov 1:932–933
Knieps S, Dove S, Michel MC et al. (1996) ω-Phenyl-ω-(2-pyridyl)alkyl-substituted bisguanidines are moderate neuropeptide Y antagonists. Pharm Pharmacol Lett 6:27–30
Kordik CP, Lovenberg TW, Reitz A, Ortho-McNeil Pharm. (2000) Preparation of pyrazole carboxamides for the treatment of obesity and other disorders. Patent WO 0069849
Kordik CP, Luo C, Zanoni BC et al. (2001) Aminopyrazoles with high affinity for the human neuropeptide Y5 receptor. Bioorg Med Chem Lett 11:2283–2286
Lecklin A, Lundell I, Paananen L et al. (2002) Receptor subtypes Y1 and Y5 mediate neuropeptide Y induced feeding in the guinea-pig. Br J Pharmacol 135:2029–2037
Ling AL (1999) Neuropeptide Y receptor antagonists. Expert Opin Ther Pat 9:375–384
Linn J, Aquino C, Dezube M (2001) Benzimidazole neuropeptide Y Y5 antagonists: rapid SAR development using a solid phase approach. 222nd ACS National Meeting. Chicago, August 2001: (abstract MEDI-027)
Malmström RE, Balmer KC, Lundberg JM (1997) The neuropeptide Y (NPY) Y1 receptor antagonist BIBP 3226: equal effects on vascular responses to exogenous and endogenous NPY in the pig in vivo. Br J Pharmacol 121:595–603
Malmström RE, Alexandersson A, Balmer KC et al. (2000) In vivo characterization of the novel neuropeptide Y Y1 receptor antagonist H 409/22. J Cardiovasc Pharmacol 36:516–525
Malmström RE (2000) Neuropeptide Y Y1 receptor mediated mesenteric vasoconstriction in the pig in vivo. Regul Pept 95:59–63
Malmström RE (2001a) Vascular pharmacology of BIIE0246, the first selective non-peptide neuropeptide Y Y2 receptor antagonist, in vivo. Br J Pharmacol 133:1073–1080
Malmström RE, Balmer KC, Weilitz J et al. (2001) Pharmacology of H 394/84, a dihydropyridine neuropeptide Y Y(1) receptor antagonist, in vivo. Eur J Pharmacol 418:95–104.
Malmström RE (2001b) Existence of both neuropeptide Y, Y1 and Y2 receptors in pig spleen: evidence using subtype-selective antagonists in vivo. Life Sci 69:1999–2005
Malmström RE, Lundberg JN, Weitzberg E (2002a) Effects of the neuropeptide Y Y2 receptor antagonist BIIE0246 on sympathetic transmitter release in the pig in vivo. Naunyn Schmiedebergs Arch Pharmacol 365:106–111
Malmström RE, Lundberg JO, Weitzberg E (2002b) Autoinhibitory function of the sympathetic prejunctional neuropeptide Y Y(2) receptor evidenced by BIIE0246. Eur J Pharmacol 439:113–119
Malmström RE (2002) Pharmacology of neuropeptide Y receptor antagonists. Focus on cardiovascular functions. Eur J Pharmacol 447:11–30
Marzabadi MR, Wong WC, Noble SA, Synaptic Pharm. Corp., USA (2000a) Preparation of benzo[2,3]thiepino[4,5-d]thiazol-2-ylaminoalkylsulfonamides and related compounds as selective neuropeptide Y (Y5) antagonists. Patent US 6124331
Marzabadi MR, Wong WC, Noble SA et al, Synaptic Pharm. Corp., USA. (2000b) Preparation of triazineamines, thiazolamines, and benzo[2,3]thiepino[4,5-d][l,3]thiazol-2-ylamines as selective NPY (Y5) antagonists. Patent WO 0064880
Marzabadi MR, Wong WC, Noble SA et al., Synaptic Pharm. Corp., USA; Novartis A.-G. (2001) Preparation of selective NPY (Y5) antagonists and pharmaceutical compositions thereof for treating an abnormality modulated by human Y5 receptor activity. Patent WO 0102379
McCombie S, Stamford AW, Huang Y et al., Schering-Plough Corp., USA (2002) Substituted urea neuropeptide Y Y5 receptor antagonists. Patent US 2002165223
McNally J J, Youngman MA, Lovenberg TW et al. (2000a) N-acylated alpha-(3-pyridylmethyl)-beta-aminotetralin antagonists of the human neuropeptide Y Y5 receptor. Bioorg Med Chem Lett 10:1641–1643
McNally JJ, Youngman MA, Lovenberg TW et al. (2000b) N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines: potent antagonists of human neuropeptide Y Y5 receptor. Bioorg Med Chem Lett 10:213–216
Meister A (1999) Pharmacological characterization of new histamine and neuropeptide Y receptor ligands: set-up and validation of functional test models on isolated organs. Doctoral thesis, University of Regensburg, Regensburg, Germany
Michel MC, Motulsky HJ (1990) He 90481: A compeptitive nonpeptidergic antagonist at neuropeptide Y receptors. Ann N Y Acad Sci 611:392–394
Michel MC, Moersdorf JP, Engler H et al., Heumann Pharma G.m.b.H. und Co., Germany (1991) Use of guanidine derivatives for the manufacture of a medicament with neuropeptide Y-antagonistic activity. Patent EP448765
Michel MC, Dove S, Buschauer A (1993) Arpromidine and related histamine H2 agonists as chemical leads for the development of non-peptide neuropeptide Y antagonists. Arch Pharm (Weinheim) 326:664
Michel MC, Beck-Sickinger AG, Cox H et al. (1998) XVI. International Union of Pharmacology Recommandations for the Nomenclature of Neuropeptide Y, Peptide YY, and Pancreatic Polypeptide Receptors. Pharmacological Reviews 50:143–150
Mollereau C, Gouarderes C, Dumont Y et al. (2001) Agonist and antagonist activities on human NPFF(2) receptors of the NPY ligands GR231118 and BIBP3226. Br J Pharmacol 133:1–4
Mollereau C, Mazarguil H, Marcus D et al. (2002) Pharmacological characterization of human NPFF(l) and NPFF(2) receptors expressed in CHO cells by using NPY Y(1) receptor antagonists. Eur J Pharmacol 451:245–256
Morgan DGA, Small CJ, Abusnana S et al. (1998) The NPY Y1 receptor antagonist BIBP 3226 blocks NPY induced feeding via a non-specific mechanism. Regul Pept 75/76:377–382
Moser C, Bernhardt G, Michel J et al. (2000) Cloning and functional expression of the hNPY Y5 receptor in human endometrial cancer (HEC-1B) cells. Can J Physiol Pharmacol 78:134–142
Müller M, Knieps S, Gessele K et al. (1997) Synthesis and neuropeptide Y Y1 receptor antagonistic activity of N,N-disubstituted ω-guanidino-and ω-aminoalkanoic acid amides. Arch Pharm (Weinheim) 330:333–342
Murakami Y, Hagishita S, Okada T et al. (1999a) 1,3-disubstituted benzazepines as neuropeptide Y Y1receptor antagonists. Bioorg Med Chem 7:1703–1714
Murakami Y, Hara H, Okada T et al. (1999b) 1,3-Disubstituted benzazepines as novel, potent, selective neuropeptide Y Y1 receptor antagonists. J Med Chem 42:2621–2632
Nishikawa N, Aoki K, Suzuki M et al., Meiji Seika Kaisha Ltd., Japan (2000) Tricyclic compounds. Patent WO 0063171
Norman MH, Chen N, Han N et al., Amgen Inc., USA (1999) Preparation of bicyclic pyridine and pyrimidine derivatives as neuropeptide Y receptor antagonists. Patent WO 9940091
Norman MH, Chen N, Chen Z et al. (2000) Structure-Activity Relationships of a Series of Pyrrolo[3,2-d]pyrimidine derivatives and related compounds as neuropeptide Y5 receptor antagonists. J Med Chem 43:4288–4312
Palczewski K, Kumasaka T, Hori T et al. (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745
Palea S, Corsi M, Rimland JM et al. (1995) Discrimination by benextramine between the NPY-Y1 receptor subtypes present in rabbit isolated vas deferens and saphenous vein. Br J Pharmacol 115:3–10
Parker E, Van Heek M, Stamford A (2002) Neuropeptide Y receptors as targets for antiobesity drug development: perspective and current status. Eur J Pharmacol 440:173–187
Peterson JM, Blum CA, Cai G et al., Pfizer Inc., USA (1996) Certain substituted benzylamine derivatives: a new class of neuropeptide Y1 specific ligands. Patent WO 9640660
Pheng LH, Quirion R, Iyengar S et al. (1997) The rabbit ileum: a sensitive and selective preparation for the neuropeptide Y Y5 receptor. Eur J Pharmacol 333:R3–5
Poindexter GS, Bruce M, Johnson G et al, Bristol-Myers Squibb Company, USA (1996) Dihydropyridine NPY antagonists: piperazine derivatives. Patent EP 747356
Poindexter GS, Gillman K, Bristol-Myers Squibb Company, USA (1999a) Imidazolone anorectic agents: III. heteroaryl derivatives. Patent WO 9948873
Poindexter GS, Gillman K, Bristol Myers Squibb Co., USA (1999b) Imidazolone anorectic agents: I. acyclic derivatives. Patent WO 9948888
Poindexter GS, Antal I, Guipponi LM et al., Bristol-Myers Squibb Co. (1999) Imidazolone anorectic agents: II. phenyl derivatives. Patent WO 9948888
Poindexter GS, Antal I, Giupponi LM et al., Bristol-Myers Squibb Company, USA (2001) NPY antagonists: spiroisoquinolinone derivatives. Patent WO 0113917
Poindexter GS, Bruce MA, LeBoulluec KL et al. (2002) Dihydropyridine neuropeptide Y Y(l) receptor antagonists. Bioorg Med Chem Lett 12:379–382
Polidori C, Ciccocioppo R, Regoli D et al. (2000) Neuropeptide Y receptor(s) mediating feeding in the rat: characterization with antagonists. Peptides 21:29–35
Rabinovich A, Mazurov A, Krokhina G et al. (1997) Discovery of Neuropeptide Y Receptor Antagonists. In: Grundemar L, Bloom S (eds) Neuropeptide Y and drug development. Academic Press, London, San Diego, pp 191–201
Ramanjulu J, Aquino C, Palazzo F et al. (2001) Synthesis and structure activity studies of bisheteroaryl guanidines as NPY-Y5 antagonists. 221st ACS National Meeting. San Diego, April 2001 (abstract MEDI-210)
Robin-Jagerschmidt C, Sylte I, Bihoreau C et al. (1998) The ligand binding site of NPY at the rat Y1 receptor investigated by site-directed mutagenesis and molecular modeling. Mol Cell Endocrinol 139:187–198
Rudolf K, Eberlein W, Wieland HA et al. (1994a) The first highly potent and selective non-peptide NPY Y1 receptor antagonist: BIBP 3226. Eur J Pharm 271:R11–13
Rudolf K, Eberlein W, Engel W et al, (Dr. Karl Thomae GmbH, Germany). (1994b) Preparation of amino acid derivatives as neuropeptide Y antagonists. Patent WO 19940118
Rudolf K, Eberlein W, Engel W et al., Boehringer Ingelheim Pharma K.-G., Germany (1999) Preparation of piperazine-containing peptidomimetics for use as NPY antagonists. Patent DE 19816889
Rudolf K, Eberlein W, Engel W et al. (1997) BIBP3226, a potent and selective neuropeptide Y Y1-receptor antagonist. Structure-activity studies and localization of the human Y1 receptor binding site. In: Grundemar L, Bloom S (eds) Neuropeptide Y and drug development. Academic Press, London, San Diego, pp 175–190
Rüeger H, Schmidlin T, Rigollier P et al., Novartis AG (1997a) Quinazoline-2,4-diazirines as NPY receptor antagonists. Patent WO 9720822
Rüeger H, Schmidlin T, Rigollier P et al., Novartis AG (1997b) Quinazoline derivatives useful as antagonists of NPY receptor subtype Y5. Patent WO 9720820
Rüeger H, Schmidlin T, Rigollier P et al, Novartis AG (1997c) Heteroaryl Derivatives. Patent WO 9720821
Rüeger H, Rigollier P, Yamaguchi Y et al. (2000) Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y5 receptor antagonists. Bioorg Med Chem Lett 10:1175–1179
Salaneck E, Holmberg SK, Berglund MM et al. (2000) Chicken neuropeptide Y receptor Y2: structural and pharmacological differences to mammalian Y2(1). FEBS Lett 484:229–234
Sato N, Takahashi T, Shibata T et al. (2003) Design and Synthesis of the Potent, Orally Available, Brain-Penetrable Arylpyrazole Class of Neuropeptide Y5 Receptor Antagonists. J Med Chem 46:666–669
Satoh Y, Hatori C, Ito H (2002) Novel potent antagonists of human neuropeptide Y-Y5 receptor. Part 4: tetrahydrodiazabenzazulene derivatives. Bioorg Med Chem Lett 12:1009–1011
Sautel M, Rudolf K, Wittneben H et al. (1996) Neuropeptide Y and the nonpeptide antagonist BIBP 3226 share an overlapping binding site at the human Y1 receptor. Mol Pharmacol 50:285–292
Schmidlin T, Rüeger H, Gerspacher M, Novartis A.-G., Switzerland (2001) Preparation of condensed thiazolamines as neuropeptide Y5 antagonists. Patent WO 0164675
Serradeil-Le Gal C, Valette G, Rouby P-E et al. (1995) SR120819A, an orally-active and selective neuropeptide Y Y1 receptor antagonist. FEBS Lett 362:192–196
Serradeil-Le Gal C (1997) SR 120819A or the first generation of orally active Y1 receptor antagonists. In: Grundemar L, Bloom SR (eds) Neuropeptide Y and drug development. Academic Press, London, San Diego, pp 157–174
Shigeri Y, Ishikawa M, Ishihara Y et al. (1998) A potent nonpeptide neuropeptide Y Y1 receptor antagonist, a benzodiazepine derivative. Life Sci 63:PL151–160
Silva AP, Cavadas C, Grouzmann E (2002) Neuropeptide Y and its receptors as potential therapeutic drug targets. Clin Chim Acta 326:3–25
Sit SY, Huang Y, Antal-Zimanyi I et al. (2002) Novel dihydropyrazine analogues as NPY antagonists. Bioorg Med Chem Lett 12:337–340
Smith-White MA, Hardy TA, Brock JA et al. (2001) Effects of a selective neuropeptide Y Y2 receptor antagonist, BIIE0246, on Y2 receptors at peripheral neuroeffector junctions. Br J Pharmacol 132:861–868
Stamford AW, Dugar S, Wu Y et al., Schering Corp., USA (1999) Neuropeptide Y5 receptor antagonists. Patent WO 9964394
Stamford AW, Dugar S, Wu Y et al., Schering Corp., USA (2001) Neuropeptide Y5 receptor antagonists. Patent US 6329395
Stamford AW, Huang Y, Kelly JM et al, Schering Corp., USA (2002a) Substituted urea neuropeptide Y Y5 receptor antagonists. Patent WO 0222592
Stamford AW, Dong Y, McCombie S, Schering Corp., USA (2002b) Heteroaryl urea neuropeptide Y Y5 receptor antagonists. Patent WO 0249648
Sylte I, Robin-Jagerschmidt C, Bihoreau C et al. (1998) Molecular modeling of the NPY binding site on the Y1 receptor. J Mol Model 4:221–233
Sylte I, Andrianjara CR, Calvet A et al. (1999) Molecular dynamics of NPY Y1 receptor activation. Bioorg Med Chem 7:2737–2748
Tabuchi S, Itani H, Sakata Y et al. (2002) Novel potent antagonists of human neuropeptide Y Y5 receptor. Part 1:2-oxobenzothiazolin-3-acetic acid derivatives. Bioorg Med Chem Lett 12:1171–1175
Thurkauf A, Yuan J, Hutchison A et al, Neurogen Corp.; Pfizer Inc. (1999) Preparation of diarylimidazoles as neuropeptide Y receptor ligands. Patent WO 9901128
Turnbull AV, Ellershaw L, Masters DJ et al. (2002) Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats. Diabetes 51:2441–2449
Walker P, Munoz M, Martinez R et al. (1994) Acidic residues in extracellular loops of the human Y1 neuropeptide Y receptor are essential for ligand binding. J Biol Chem 269:2863–2869
Wieland HA, Willim KD, Entzeroth M et al. (1995) Subtype selectivity and antagonistic profile of the nonpeptide Y1 receptor antagonist BIBP 3226. J Pharmacol Exp Ther 275:143–149
Wieland HA, Engel W, Eberlein W et al. (1998) Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents. Br J Pharmacol 125:549–555
Wright J, Bolton G, Creswell M et al. (1996) 8-Amino-6-(arylsulfonyl)-5-nitroquinolines: novel nonpeptide neuropeptide Y1 receptor antagonists. Bioorg Med Chem Lett 6:1809–1814
Wright J (1997) Design and discovery of neuropeptide Y1 receptor antagonists. Drug Discovery Today 2:19–24
Yokosuka M, Dube MG, Kalra PS et al. (2001) The mPVN mediates blockade of NPY-induced feeding by a Y5 receptor antagonist: a c-FOS analysis. Peptides 22:507–514
Youngman MA, McNally JJ, Lovenberg TW et al. (2000) alpha-Substituted N-(sulfonamido) alkyl-beta-aminotetralins: potent and selective neuropeptide Y Y5 receptor antagonists. J Med Chem 43:346–350
Zarrinmayeh H, Nunes AM, Ornstein PL et al. (1998) Synthesis and evaluation of a series of novel 2-[(4-chlorophenoxy)methyl]benzimidazoles as selective neuropeptide Y Y1 receptor antagonists. J Med Chem 41:2709–2719
Zarrinmayeh H, Zimmerman DM, Cantrell BE et al. (1999) Structure-activity relationship of a series of diaminoalkyl substituted benzimidazole as neuropeptide Y Y1 receptor antagonists. Bioorg Med Chem Lett 9:647–652
Zimanyi IA, Poindexter GS (2000) NPY-ergic agents for the treatment of obesity. Drug Dev Res 51:94–111
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2004 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Brennauer, A., Dove, S., Buschauer, A. (2004). Structure-Activity Relationships of Nonpeptide Neuropeptide Y Receptor Antagonists. In: Michel, M.C. (eds) Neuropeptide Y and Related Peptides. Handbook of Experimental Pharmacology, vol 162. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18764-3_17
Download citation
DOI: https://doi.org/10.1007/978-3-642-18764-3_17
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-62282-3
Online ISBN: 978-3-642-18764-3
eBook Packages: Springer Book Archive