Design of subtype selective melatonin receptor agonists and antagonists.
Studies of the physiological actions of melatonin have been hindered by the lack of specific, potent and subtype selective agonists and antagonists. In the present study, we describe the utility of a melanophore cell line from Xenopus laevis for exploring structure-activity relationships among novel melatonin analogues and report a novel MT2-selective agonist (IIK7) and MT2-selective receptor antagonist (K185). IIK7 is a potent melatonin receptor agonist in the melanophore model, and in NIH3T3 cells expressing human mt1 and MT2 receptor subtypes. In radioligand binding experiments IIK7 is 90-fold selective for the MT2 subtype. K185 is devoid of agonist activity, but acts as a competitive melatonin antagonist in melanophores. A low concentration (10(-9) M) antagonizes melatonin inhibition of forskolin stimulation of cyclic AMP in NIH3T3 cells expressing human MT2 receptors, but has no effect in cells expressing mt1 receptors. In binding assays, K185 is 140-fold selective for the MT2 subtype.
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Physiology Division, GKT School of Biomedical Science, King's College London, UK. david.sugden@kcl.ac.uk
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D016475:3T3 Cells; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D054833:Isoindoles; D008543:Melanins / Q000378:metabolism; D008547:Melanophores / Q000187:drug effects / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D044094:Receptors, Melatonin; D011993:Recombinant Fusion Proteins / Q000187:drug effects; D015290:Second Messenger Systems / Q000187:drug effects; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*; D014363:Tryptamines / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
C114459:4-phenyl-2-propionamidotetraline; C121416:GR 135533; C121417:IIK7; D007211:Indoles; D054833:Isoindoles; C121418:K 185; D008543:Melanins; C121415:N-(2-naphth-1-yl-ethyl)cyclopropyl carboxamide; D009281:Naphthalenes; D020033:Protein Isoforms; D011759:Pyrrolidines; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D011993:Recombinant Fusion Proteins; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; C057154:luzindole; D005576:Colforsin; D000242:Cyclic AMP; D008550:Melatonin; D015056:1-Methyl-3-isobutylxanthine