Peptidvl MC4R Agonists - All endogenous ligands contain a conserved peptide fragment - His6-Phe7-Arg8-Trp9 (a-MSH numbering) - which has been identified as the "active core" or "message sequence" responsible for interaction with the melanocortin receptors. a-MSH is a 13 amino acid peptide agonist at all melanocortin receptors.
Structure-activity studies identified [Nle ,DPhe7]a-MSH (NDP-a-MSH, MT-I) - a more potent and enzyme-resistant analog with D-Phe substitution at position 7 (23). This and its radiolabeled iodo-analog have quickly become valuable tools in melanocortin receptor studies. A smaller, cyclized variant maintaining the active core of NDP-a-MSH was subsequently discovered (24). This lactam, MT-II (1), is a very potent and nonselective agonist at hMC1R, hMC3R, hMC4R and hMC5R.
Acvclic Peptides - Truncated analogs of a-MSH bearing the "message sequence" have been used extensively to probe receptor binding and activation. The tetrapeptide sequence has been modified in various ways by replacing each of the amino acids and/or altering the N/C-terminal moieties. Of relevance to this review are alterations that have afforded improved MC4R selectivity (25-32).
Analogs containing the tetrapeptide core, modified by an additional amino acid and hydrophobic N-terminus have shown excellent selectivity against hMC3R and hMC5R. Ro27-3225 (2) and a pentapeptide (3) are both potent hMC4R/hMC1 R agonists with little or no activity at hMC3R and hMC5R (25,26).
Replacement of the His6 residue in the linear tetrapeptide impacted mMC3R selectivity (27). Ac-Anc6-DPhe7-Arg8-Trp9-NH2, containing an amino-2-naphthylcarboxylic acid in place of His6, was reported to be a potent agonist at mMC4R with over 4700-fold selectivity against mMC3R. The compound is also selective against mMC1R but not against mMC5R. The use of rigid non-basic His6 surrogates in the pentapeptide (3) dialed out hMC1R activity (32). Substituted 2-aminotetraline-2-carboxylic acid containing compounds were reported to be potent agonists at hMC4R and inactive at the other subtypes (e.g. Penta-5-BrAtc6-DPhe7-Arg8-Trp9-Gly10-NH2). Improvements in selectivity over mMC3R have been realized by altering either Phe7, Arg8 or Trp9 residues or through the use of an aromatic N-terminal "cap" on the linear tetrapeptide (28-31).
Cyclic Peptides - Extensive structure-activity studies have also been carried out on the cyclic lactam 1.. Improvements in selectivity have again been afforded by alteration of the "core" amino acids as well as variation of the linker and/or N-teminus (33-37). Excision of the N-terminal fragment is effective in increasing hMC4R selectivity. Replacement of Nle4 with Pro led to [Pro^MT-ll with similar hMC4R activity to the parent lactam but 400-fold lower potency at hMC5R and 20fold reduced potency at hMC3R (33).
Large improvements in hMC4R selectivity have come from the introduction of two new templates: The first involves the use of a succinyl linker forming amide bonds between the a-amine of His6 and the amino acid at position 10. For example, cyclo(COCH2CH2CO-His6-DPhe7-Arg8-Trp9-Dab10)-NH2 is a potent hMC4R agonist with 55-fold selectivity over hMC3R and >1000-fold selectivity against hMC5R (34,35). The second involves the formation of an amide bond between the y-carboxyl group of Glu10 and the amino group of co-amino acids. For example, cyclo(NHCH2CH2CO-His6-DPhe7-Arg8-Trp -Glu1 °)-NH2 is potent at hMC4R with 90fold selectivity over hMC3R and >2000-fold selectivity over hMC5R (24).
Replacement of the His6 residue in 1 with Ala had little effect on activity at either of hMC3R-5R (36). However, using a related cyclic peptide, replacement of the amino acid with substituted 2-aminotetraline-2-carboxylic acids led to potent hMC4R agonists with inactive or weak agonist properties at hMC1R, hMC3R and hMC5R. One example is Penta-cyclo(Asp-5-CIAtc6-DPhe7-Arg8-Trp9-Lys10)-NH2 (37).
There have been a large number of patent applications issued covering peptide agonists of MC4R. These have been summarized in a recent review, and a few recent applications have been disclosed since then (38-41).
Small Molecule MC4R Agonists - To date there have been few publications reporting the discovery of potent and selective small molecule hMC4R agonists. Leads that have emerged come from both rational design and HTS with development proceeding via classical medicinal chemistry techniques (20,42-44).
Peptidyl-privileged structure based compounds have had significant success in recent years as agonists of G-protein coupled receptors. Their design is based upon the observation of commonly recurring structural elements in receptor ligands. This approach was extended to the development of an hMC4R agonist. Compound 4 is the first to be disclosed (20,42). It is a potent hMC4R agonist (EC5o = 2 nM) with >1300-fold selectivity over hMCIbR, >1100-fold selectivity over hMC3R and >350-fold selectivity over hMC5R. In vivo studies with 4 showed significant reductions in rat food intake. The compound has pro-erectile activity in a number of rodent models, providing evidence for the role of the MC4 receptor in sexual function (20,42,43).
A series of 2,3-diaryl-5-anilino[1,2,4]thiadiazoles were developed from an HTS lead (44). Optimization of the lead generated more potent compounds exemplified by 5 with an ICso of 22 nM. While the compound was reported to be an agonist, no EC50 was given. Additionally, selectivity against the other subtypes was not reported. Compound 5 showed significant reductions of food intake in fasted rat when dosed i.p. but had no effect p.o., reflecting its likely rapid metabolism. A more potent analog was also reported but showed no efficacy in the food intake assay.
While there are few published papers describing small molecule MC4R agonists, there have been a large number of patent applications published in the area (38,45,46). Several applications, illustrated by compound 4, cover MC4R agonists derived from the capped dipeptide template (47-57). Some focus exclusively on various substituted piperidine-based privileged structures, others focus on piperazine derivatives. The latest structure claimed in this series is compound 6 bearing a 2-azabicyclo[2.2,1]heptane-6-carboxylic acid (58). Compound 7, has a potency of 8.4 nM with 102% activation relative to a-MSH. More recently, an application covering piperazine-containing structure 8 was published (59). Six derivatives of compound 8 were reported to cause food intake reduction in fasted mice at doses of less than 30 mpk.
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