International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors

Abstract

The hormone melatonin (5-methoxy-N-acetyltryptamine) is synthesized primarily in the pineal gland and retina, and in several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Melatonin receptors receive and translate melatonin's message to influence daily and seasonal rhythms of physiology and behavior. The melatonin message is translated through activation of two G protein-coupled receptors, MT(1) and MT(2), that are potential therapeutic targets in disorders ranging from insomnia and circadian sleep disorders to depression, cardiovascular diseases, and cancer. This review summarizes the steps taken since melatonin's discovery by Aaron Lerner in 1958 to functionally characterize, clone, and localize receptors in mammalian tissues. The pharmacological and molecular properties of the receptors are described as well as current efforts to discover and develop ligands for treatment of a number of illnesses, including sleep disorders, depression, and cancer.

Fig. 1.

Regulation of melatonin production and receptor function. Melatonin is synthesized in the pineal gland and in the retina. In the pineal gland, melatonin (MLT) synthesis follows a rhythm driven by the suprachiasmatic nucleus, the master biological clock. Neural signals from the SCN follow a multisynaptic pathway to the superior cervical ganglia. Norepinephrine released from postganglionic fibers activates α₁- and β₁-adrenoceptors in the pinealocyte, leading to increases in second messengers (i.e., cAMP and inositol trisphosphate) and the activity of AA-NAT, the rate-limiting step in melatonin synthesis. The system is dramatically inhibited by light, the external cue that allows entrainment to the environmental light/dark cycle. The photic signal received by the retina is transmitted to the SCN via the retinohypothalamic tract, which originates in a subset of retinal ganglion cells. Pineal melatonin thus serves as the internal signal that relays day length, allowing regulation of neuronal activity (MT₁) and circadian rhythms (MT₁, MT₂) in the SCN (Dubocovich, 2007), of neurochemical function in brain through the MT₁ and MT₂ receptors (Dubocovich, 2006), of vascular tone through activation of MT₁ (constriction) and MT₂ receptors (dilation) in arterial beds (Masana et al., 2002), and seasonal changes in reproductive physiology and behavior through activation of MT₁ receptors in the pars tuberalis (Duncan, 2007). The pars tuberalis of the pituitary gland interprets this rhythmic melatonin signal and generates a precise cycle of expression of circadian genes through activation of MT₁ receptors. Melatonin synthesis in the photoreceptors of the retina follows a similar circadian rhythm generated by local oscillators (Tosini et al., 2007). Activation of MT₁ and MT₂ melatonin receptors regulate retina function and hence transmission of photic information to the brain (Dubocovich et al., 1997). [Adapted from Dubocovich ML and Masana M (2003) Melatonin receptor signaling, in Encyclopedia of Hormones and Related Cell Regulators (Henry H and Norman A eds), pp 638–644, Academic Press, San Diego, CA. Copyright © 2003 Academic Press. Used with permission.]

Fig. 2.

Melatonin synthesis. Melatonin (MLT) is synthesized from serotonin through two enzymatic steps. First, serotonin is acetylated by NAT to yield N-acetylserotonin (NAS). The second step involves transfer of a methyl group from (S)-adenosylmethionine to the 5-hydroxyl group of N-acetylserotonin via the enzyme HIOMT. The rhythms of melatonin and serotonin have opposite phase during subjective night and day (Klein, 1999).

Fig. 3.

Membrane topology of the hMT₁ melatonin receptor showing amino acids conserved in the hMT₂ receptor. Gray circles denote amino acids identical in the hMT₁ and hMT₂ melatonin receptors. The two glycosylation sites on the hMT₁ receptor are denoted (Y) in the N terminus. [Adapted from Reppert SM and Weaver DR (1995) Melatonin madness. Cell 83:1059–1062. Copyright © 1995 Elsevier Inc. Used with permission.]

Fig. 4.

MT₁ and MT₂ melatonin receptor dendrogram. Phylogenetic tree of melatonin receptor or melatonin receptor-related (GPR50, melatonin-related receptor or H9) sequences. The evolutionary distances between the different sequences were calculated with the matrix of Blosum 62 score. The tree was drawn using the Unweighted Pair Group Method with Arithmetic mean (UPGMA). GenBank accession numbers and the number of amino acids for each receptor are as follows: human H9: U52219, 613; sheep H9: U52221, 613; mouse H9: AF065145, 791; cattle MT₁: U73327, 257; sheep MT₁: U14109, 366; Djungarian hamster MT₁: U14110, 353; golden hamster MT₁: AF061158, 325; mouse MT₁: U52222, 353; rat MT₁: AF130341, 326; human MT₁: U14108, 350; Pig MT₁: U73326, 154; mouse MT₂: AY145850, 365; rat MT₂: U28218, 120; human MT₂: U25341, 362. The sequences for cattle and pig MT₁ receptors have been partially cloned.

Fig. 5.

MT₁ and MT₂ melatonin receptor 3 dimensional models and putative mode of binding for melatonin. A and B show critical amino acids residues for melatonin binding to the MT₁ and MT₂ melatonin receptors, respectively. The amino acids labeled in white have been defined by site-directed mutagenesis to modulate binding affinity (see Table 2 and 3). C and D show interactions among melatonin and key amino acid residues important for binding to the MT₁ and MT₂ melatonin receptors, respectively. [Adapted from Farce A, Chugunov AO, Logé C, Sabaouni A, Yous S, Dilly S, Renault N, Vergoten G, Efremov RG, Lesieur D, and Chavatte P (2008) Homology modelling of MT1 and MT2 receptors. Eur J Med Chem 43:1926–1944. Copyright © 2008 Elsevier Masson SAS. Used with permission.]

Fig. 6.

MT₁ and MT₂ melatonin receptor signaling. A, melatonin (MLT) signals through activation of the MT₁ receptor via two parallel pathways mediated by the α-subunit (i.e., inhibition of cAMP formation) and the βγ-subunits [i.e., potentiation of phosphoinositide turnover stimulated by a G_q-coupled receptor (R)] of G_i. B, signaling pathways coupled to MT₂ melatonin receptor activation. Melatonin-mediated phase shifts of circadian rhythms through MT₂ receptors are mediated by PKC activation (the mechanism leading to PKC activation remains putative, however). DAG, diacylglycerol; PKA, protein kinase A; R, G_q-coupled receptor (i.e., prostaglandin F_2α receptor FP and purinergic receptor P2Y) (Masana and Dubocovich, 2001). [Adapted from Masana MI and Dubocovich ML (2001) Melatonin receptor signaling: finding the path through the dark. Sci STKE 2001:pe39. Copyright © 2001 American Association for the Advancement of Science. Used with permission.]

Fig. 7.

Chemical structure of melatonin receptor ligands. A, chemical structures of nonselective MT₁/MT₂ ligands. B, chemical structures of selective MT₁ melatonin receptor ligands. C, chemical structures of selective MT₂ melatonin receptor ligands. Chemical names (see also the abbreviations list at the bottom of the first page of the article): compound 11, 1-(cyclopropylcarbonyl)-4-[(1R)-6-methoxy-2,3-hidro-1H-inden-1-yl]piperazine; compound 12, N-[(1-p-chlorobenzyl-4-methoxy-1H-indol-2-yl)methyl]propanamide; compound 13, (R)-4-(2.3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine carboxamide; DH 97, N-pentanoyl-2-benzyltryptamine; GR 128107, 3-(1-acetyl-3-piperidinyl)-5-methoxyindole; GR 135533, 3-(N-ethyl-2-pyrrolidinone)5-methoxyindole; GR 196429, N-(2-[2,3,7,8-tetrahydro-1H-furo{2,3-g}indol-1-yl]ethyl)acetamide; IIK7, N-butanoyl-2-(2-methoxy-6H-isoindolo [2,1-a]indol-11-yl)ethanamine; K185, N-butanoyl-2-(5,6,7-trihydro-11-methoxybenzo[3,4]cyclohept[2,1-a]indol-13-yl) ethanamine; luzindole, 2-benzyl-N-acetyltryptamine; LY 156735, N-[2-(6-chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide; N 0889, 2-benzyl-N-propionyl-acetyltryptamine; N 0891, 2-(p-methyl-benzyl)-N-acetyltryptamine; S 20098, N-(2-[7-methoxy-1-naphthalenyl]ethyl)acetamide; S 20928, N-[2-naphth-1-yl-ethyl]-cyclobutyl carboxamide; S 22153, N-[2-(5-ethylbenzo[b]thiophen-3-yl)ethyl]acetamide; S 24014, N-[2-(2-(3-methoxybenzyl)5-methoxy benzo(b)furan-3-yl)ethyl]acetamide; S 24635, N-[2-(5-carbamoylbenzofuran-3-yl)ethyl]acetamide; S 24773, N-{2-[3-(3-aminophenyl)-7-methoxy-1-naphthyl]ethyl}acetamide; S 25726, N-methyl-(3-{2-[(cyclopropylcarbonyl)amino]ethyl}benzo[b]furan-5-yl)carbamate; S 25567, (R,S)-N-[2-(6-hexyloxy-3,4 dihydro-2H-1-benzopyran-4-yl)ethyl]acetamide; S 26131, N-(2-{7-[3-({8-[2-acetylamino) ethyl]-2-naphtyl}oxy)propoxy]-1-naphthyl}ethyl)acetamide; S 26284, N-(2-{7-[4-({8-[2-acetylamino)ethyl]-2-naphtyl}oxy)butoxy]-1-naphthyl}ethyl)acetamide; S 26553, N-methyl-1{1-[2-(acetylamino)ethyl]naphthalen-7-yl}carbamate; S 27533, N-[2-(5-methoxy-1-methyl-4-nitroindol-3-yl)ethyl]acetamide; S 28407, N-[2-(7-methoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]cyclobutyl carboxamide; TAK-375, (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethyl]propionamide.

Fig. 7.

Chemical structure of melatonin receptor ligands. A, chemical structures of nonselective MT₁/MT₂ ligands. B, chemical structures of selective MT₁ melatonin receptor ligands. C, chemical structures of selective MT₂ melatonin receptor ligands. Chemical names (see also the abbreviations list at the bottom of the first page of the article): compound 11, 1-(cyclopropylcarbonyl)-4-[(1R)-6-methoxy-2,3-hidro-1H-inden-1-yl]piperazine; compound 12, N-[(1-p-chlorobenzyl-4-methoxy-1H-indol-2-yl)methyl]propanamide; compound 13, (R)-4-(2.3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine carboxamide; DH 97, N-pentanoyl-2-benzyltryptamine; GR 128107, 3-(1-acetyl-3-piperidinyl)-5-methoxyindole; GR 135533, 3-(N-ethyl-2-pyrrolidinone)5-methoxyindole; GR 196429, N-(2-[2,3,7,8-tetrahydro-1H-furo{2,3-g}indol-1-yl]ethyl)acetamide; IIK7, N-butanoyl-2-(2-methoxy-6H-isoindolo [2,1-a]indol-11-yl)ethanamine; K185, N-butanoyl-2-(5,6,7-trihydro-11-methoxybenzo[3,4]cyclohept[2,1-a]indol-13-yl) ethanamine; luzindole, 2-benzyl-N-acetyltryptamine; LY 156735, N-[2-(6-chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide; N 0889, 2-benzyl-N-propionyl-acetyltryptamine; N 0891, 2-(p-methyl-benzyl)-N-acetyltryptamine; S 20098, N-(2-[7-methoxy-1-naphthalenyl]ethyl)acetamide; S 20928, N-[2-naphth-1-yl-ethyl]-cyclobutyl carboxamide; S 22153, N-[2-(5-ethylbenzo[b]thiophen-3-yl)ethyl]acetamide; S 24014, N-[2-(2-(3-methoxybenzyl)5-methoxy benzo(b)furan-3-yl)ethyl]acetamide; S 24635, N-[2-(5-carbamoylbenzofuran-3-yl)ethyl]acetamide; S 24773, N-{2-[3-(3-aminophenyl)-7-methoxy-1-naphthyl]ethyl}acetamide; S 25726, N-methyl-(3-{2-[(cyclopropylcarbonyl)amino]ethyl}benzo[b]furan-5-yl)carbamate; S 25567, (R,S)-N-[2-(6-hexyloxy-3,4 dihydro-2H-1-benzopyran-4-yl)ethyl]acetamide; S 26131, N-(2-{7-[3-({8-[2-acetylamino) ethyl]-2-naphtyl}oxy)propoxy]-1-naphthyl}ethyl)acetamide; S 26284, N-(2-{7-[4-({8-[2-acetylamino)ethyl]-2-naphtyl}oxy)butoxy]-1-naphthyl}ethyl)acetamide; S 26553, N-methyl-1{1-[2-(acetylamino)ethyl]naphthalen-7-yl}carbamate; S 27533, N-[2-(5-methoxy-1-methyl-4-nitroindol-3-yl)ethyl]acetamide; S 28407, N-[2-(7-methoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]cyclobutyl carboxamide; TAK-375, (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethyl]propionamide.

Fig. 7.

Chemical structure of melatonin receptor ligands. A, chemical structures of nonselective MT₁/MT₂ ligands. B, chemical structures of selective MT₁ melatonin receptor ligands. C, chemical structures of selective MT₂ melatonin receptor ligands. Chemical names (see also the abbreviations list at the bottom of the first page of the article): compound 11, 1-(cyclopropylcarbonyl)-4-[(1R)-6-methoxy-2,3-hidro-1H-inden-1-yl]piperazine; compound 12, N-[(1-p-chlorobenzyl-4-methoxy-1H-indol-2-yl)methyl]propanamide; compound 13, (R)-4-(2.3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine carboxamide; DH 97, N-pentanoyl-2-benzyltryptamine; GR 128107, 3-(1-acetyl-3-piperidinyl)-5-methoxyindole; GR 135533, 3-(N-ethyl-2-pyrrolidinone)5-methoxyindole; GR 196429, N-(2-[2,3,7,8-tetrahydro-1H-furo{2,3-g}indol-1-yl]ethyl)acetamide; IIK7, N-butanoyl-2-(2-methoxy-6H-isoindolo [2,1-a]indol-11-yl)ethanamine; K185, N-butanoyl-2-(5,6,7-trihydro-11-methoxybenzo[3,4]cyclohept[2,1-a]indol-13-yl) ethanamine; luzindole, 2-benzyl-N-acetyltryptamine; LY 156735, N-[2-(6-chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide; N 0889, 2-benzyl-N-propionyl-acetyltryptamine; N 0891, 2-(p-methyl-benzyl)-N-acetyltryptamine; S 20098, N-(2-[7-methoxy-1-naphthalenyl]ethyl)acetamide; S 20928, N-[2-naphth-1-yl-ethyl]-cyclobutyl carboxamide; S 22153, N-[2-(5-ethylbenzo[b]thiophen-3-yl)ethyl]acetamide; S 24014, N-[2-(2-(3-methoxybenzyl)5-methoxy benzo(b)furan-3-yl)ethyl]acetamide; S 24635, N-[2-(5-carbamoylbenzofuran-3-yl)ethyl]acetamide; S 24773, N-{2-[3-(3-aminophenyl)-7-methoxy-1-naphthyl]ethyl}acetamide; S 25726, N-methyl-(3-{2-[(cyclopropylcarbonyl)amino]ethyl}benzo[b]furan-5-yl)carbamate; S 25567, (R,S)-N-[2-(6-hexyloxy-3,4 dihydro-2H-1-benzopyran-4-yl)ethyl]acetamide; S 26131, N-(2-{7-[3-({8-[2-acetylamino) ethyl]-2-naphtyl}oxy)propoxy]-1-naphthyl}ethyl)acetamide; S 26284, N-(2-{7-[4-({8-[2-acetylamino)ethyl]-2-naphtyl}oxy)butoxy]-1-naphthyl}ethyl)acetamide; S 26553, N-methyl-1{1-[2-(acetylamino)ethyl]naphthalen-7-yl}carbamate; S 27533, N-[2-(5-methoxy-1-methyl-4-nitroindol-3-yl)ethyl]acetamide; S 28407, N-[2-(7-methoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]cyclobutyl carboxamide; TAK-375, (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethyl]propionamide.