A series of cyclic lactam analogues of γ-MSH (H-Tyr 1 -Val 2 -Met 3 -Gly 4 -His 5 -Phe 6 -Arg 7 -Trp 8 -Asp 9 -Arg 10 -Phe 11 -Gly 12 -OH) with a bulky hydrophobic residue in the direct proximity to the pharmacophore (Xaa-D-Phe/D-Nal(2′)-Arg-Trp) were designed and synthesized by solid-phase methods. A variety of amino acids with a broad range of hydrophobic/hydrophilic properties was introduced in position 5 to further explore their complementary role in receptor selectivity. Biological evaluation of these peptides revealed several analogues with potent hMC3R agonist and hMC3R/ hMC5R antagonist activities, and good receptor selectivity. Analogue 4, c[Nle-Arg-D-Phe-Arg-TrpGlu]-NH 2 , was found to be a very potent and selective hMC3R agonist (EC 50 = 1.2 nM, 112% act). In addition, analogue 13, c[Nle-Val-D-Nal(2′)-Arg-Trp-Glu]-NH 2 , was identified as an hMC3R/ hMC5R antagonist with the best selectivity against the hMC4R in this series (pA 2 (hMC3R) = 8.4; pA 2 (hMC5R) = 8.7). These results indicate the significance of steric factors in melanocortin receptor selectivity and suggest that introduction of bulky residues in the direct proximity to the melanocortin pharmacophore is an effective approach to design of novel hMC3R and hMC5R selective ligands.

The insecticide methomyl, an oxime carbamate, was first introduced in 1968 for broad spectrum control of several insect classes, including Lepidoptera, Hemiptera, Homoptera, Diptera, and Coleoptera. Like other carbamates, it inhibits AChE activity, resulting in nerve and/or tissue failure and possibly death. Considered highly toxic to insects (larval and adult stages), methomyl is thought to be metabolically degraded via mixed-function oxidase(s). Methomyl has both a low vapor pressure and Henry's law constant; hence, volatilization is not a major dissipation route from either water or moist or dry soils. Photolysis represents a minor dissipation pathway; however, under catalytic conditions, degradation via photolysis does occur. Methomyl possesses a moderate-to-high water solubility; thus hydrolysis, under alkaline conditions, represents a major degradation pathway. Methomyl has a low-to-moderate sorption capacity to soil. Although results may vary with soil type and organic matter content, methomyl is unlikely to persist in complex soils. Methomyl is more rapidly degraded by microbes, and bacterial species have been identified that are capable of using methomyl as a carbon and/or nitrogen source. The main degradation products of methomyl from both abiotic and biotic processes are methomyl oxime, acetonitrile, and CO₂. Methomyl is moderately to highly toxic to fishes and very highly toxic to aquatic invertebrates. Methomyl is highly toxic orally to birds and mammals. Methomyl is classed as being highly toxic to humans via oral exposures, moderately toxic via inhalation, and slightly toxic via dermal exposure. At relatively high doses, it can be fatal to humans. Although methomyl has been widely used to treat field crops and has high water solubility, it has only infrequently been detected as a contaminant of water bodies in the USA. It is classified as a restricted-use insecticide because of its toxicity to multiple nontarget species. To prevent nontarget species toxicity or the possibility of contamination, as with all pesticides, great care should be taken when applying methomyl-containing products for agricultural, residential, or other uses.

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A variety of dicarboxylic acid linkers introduced between the α-amino group of Pro 6 and the ε-amino group of Lys 10 of the cyclic lactam α-melanocyte-stimulating hormone (α-MSH)-derived Pro 6 -DPhe7/D-Nal(2′) 7 -Arg 8 -Trp 9 -Lys 10 -NH 2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro 6 residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH 2 , EC 50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2′)-Arg-Trp-Lys]-NH 2 , IC 50 = 23 nM). Modeling experiments suggest that 2,3-pyrazinedicarboxylic acid stabilizes a β-turn-like structure with the D-Phe/D-Nal(2′) residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH 2 ) 2 -CO-Nle-D-Nal(2′)-Arg-Trp-Lys]-NH 2 , IC 50 = 12 and 17 nM, respectively), similarly to the previously described cyclic γ-melanocyte-stimulating hormone (γ-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.

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