Peptoid-peptide hybrids as potent novel melanocortin receptor ligands.

All possible peptoid-peptide hybrids of an MC4 receptor agonist were synthesized and investigated on cells expressing different melanocortin (MC) receptor subtypes and for rat grooming behavior. In general, receptor selectivity remained while affinity and potency were decreased. The length of the functional group of Trp was more important for MC3 and MC5 than for MC4 receptor binding. In general, the potency of the peptoid-peptide hybrids to increase rat excessive grooming behavior correlated well with MC4 receptor pharmacology.

Accelerating sensory recovery after sciatic nerve crush: non-selective versus melanocortin MC4 receptor-selective peptides.

Melanocortin receptor ligands accelerate functional recovery after peripheral nerve crush. It is not known which mechanism is involved or via which melanocortin receptor this effect occurs, albeit indirect evidence favours the melanocortin MC4 receptor. To test whether the melanocortin MC4 receptor is involved in the effects of melanocortins on functional recovery, we used melanocortin compounds that distinguish the melanocortin MC4 receptor from the melanocortin MC1, MC3 and MC5 receptors on basis of selectivity and agonist/antagonist profile. Activation and binding studies indicated that the previously described peptides JK1 (Ac-Nle-Gly-Lys-D-Phe-Arg-Trp-Gly-NH2) and [D-Tyr4]melanotan-II ([D-Tyr4]MTII. Ac-Nle-c[Asp-His-D-Tyr-Arg-Trp-Lys]NH2) are selective for the rat melanocortin MC4 receptor as compared to the rat melanocortin MC3 and MC5 receptors, but are also potent on the melanocortin MC1 receptor. Both peptides did not accelerate sensory recovery in rats with a sciatic nerve crush, whereas the non-selective melanocortin agonist melanotan-II (MTII, Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]NH2) was effective. The melanocortin MC3/MC4 receptor antagonist SHU9119 (Ac-Nle-c[Asp-His-D-Nal(2)-Arg-Trp-Lys]NH2) also enhanced sensory recovery. This effect was probably not due to interaction with the melanocortin MC4 receptor, since JK46 (Ac-Gly-Lys-His-D-Nal(2)-Arg-Trp-Gly-NH2), a selective melanocortin MC4 receptor antagonist, was ineffective. Taken together, these data suggest that melanocortins do not accelerate sensory recovery via interaction with the melanocortin MC4 receptor. From the known melanocortin receptors, only the involvement of the melanocortin MC5 receptor in acceleration of recovery could not be excluded.

Discovery and in vivo evaluation of new melanocortin-4 receptor-selective peptides.

The melanocortin-4 receptor (MC4R) is involved in several physiological processes, including body weight regulation and grooming behaviour in rats. It has also been suggested that the MC4R mediates the effects of melanocortin ligands on neuropathic pain. Selective compounds are needed to study the exact role of the MC4R in these different processes. We describe here the development and evaluation of new melanocortin compounds that are selective for the MC4R as compared with the other centrally expressed receptors, MC3R and MC5R. First, a library of 18 peptides, in which a melanocortin-based sequence was systematically point-mutated, was screened for binding to and activity on the MC3R, MC4R and MC5R. Compound Ac-Nle-Gly-Lys-D-Phe-Arg-Trp-Gly-NH(2) (JK1) appeared to be the most selective MC4R compound, based on affinity. This compound is 90- and 110-fold selective for the MC4R as compared to the MC3R and MC5R, respectively. Subsequent modification of JK1 yielded compound Ac-Nle-Gly-Lys-D-Nal(2)-Arg-Trp-Gly-NH(2) (JK7)(,) a selective MC4R antagonist with 34-fold MC4R/MC3R and 109-fold MC4R/MC5R selectivity. The compounds were active in vivo as determined in a grooming assay and a model for neuropathic pain in rats. Intravenous (i.v.) injections suggested that they were able to pass the blood-brain barrier.The compounds identified here will be useful in further research on the physiological roles of the MC4R.