Guoxia Han

Blockade of melanocortin transmission inhibits cocaine reward

Melanocortins and the melanocortin‐4 receptor (MC4‐R) are enriched in the nucleus accumbens, a brain region that has been implicated in the rewarding action of cocaine and other drugs of abuse. In the present study we use a number of rat behavioral models to show that infusion of a melanocortin peptide antagonist into the nucleus accumbens blocks the reinforcing, incentive motivational, and locomotor sensitizing effects of cocaine. We also show that locomotor responses to repeated cocaine exposure are completely blocked in MC4‐R null mutant mice and reduced in Agouti mice that overexpress an endogenous inhibitor of melanocortins in the brain. The results also demonstrate that cocaine administration increases the expression of MC4‐R in the nucleus accumbens and striatum, and that MC4‐R is co‐localized with prodynorphin in medium spiny neurons in the nucleus accumbens. Together, these findings indicate that the behavioral actions of cocaine are dependent on activation of MC4‐R, and suggest that upregulation of this receptor by drug exposure may contribute to sensitization of these behavioral responses. Modulation of cocaine reward is a novel action of the melanocortin–MC4‐R system and could be targeted for the development of new medications for cocaine addiction.

Extensive structure–activity studies of lactam derivatives of MT‐II and SHU‐9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5

The melanocortin system is involved in the regulation of several diverse physiologic pathways. Recently we have demonstrated that replacing His6 by Pro6 in the well-known antagonist SHU-9119 resulted in a potent agonist at the hMC5R (EC50 = 0.072 nm) with full antagonist activity at the hMC3R and the hMC4R. We have designed, synthesized, and pharmacologically characterized a series of peptide analogs of MT-II and SHU-9119 at the human melanocortin receptors MC3R, MC4R and MC5R. All these peptides were modified at position 6 with a Pro instead of a His residue. In this study, we have identified new scaffolds which are antagonists at the hMC4R and hMC3R. Additionally, we have discovered a new selective agonist at the hMC4R, Ac-Nle-c[Asp-Pro-D-Phe-Arg-Trp-Lys]-Pro-Val-NH2 (6, PG-931) which will be useful in further biologic investigations of the hMC4R. PG-931 was about 100-fold more selective for the hMC4R vs. the hMC3R (IC50 = 0.58 and 55 nm, respectively). Some of these new analogs have exceptional biologic potencies at the hMC5R and will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R.

MT‐II Induces Penile Erection via Brain and Spinal Mechanisms

Abstract: α‐Melanocyte‐stimulating hormone induces penile erection via melanocortin (MC) receptors in areas surrounding the third ventricle, but spinal and peripheral mechanisms have not been demonstrated. We used pharmacological strategies to localize the site of the proerectile action of the melanocortin receptor agonist MT‐II. We administered MT‐II intracerebroventribularly (i.c.v.), intrathecally (i.th.), and intravenously (i.v.) and scored penile erection and yawning for 90 min in awake male rats. In some animals i.c.v. or i.th. SHU‐9119 was injected 10 minutes before i.c.v. and i.th. MT‐II to confirm the MC receptor action of the agonist and to distinguish spinal from supraspinal effects. To exclude a site of action in the penis, we recorded intracorporal pressure responses to intracavernosal injection of MT‐II in the anesthetized rat. MT‐II induced penile erections in a dose‐dependent fashion, with optimal response at 1 μg for both i.c.v. and i.th. routes. Supraspinal MT‐II‐induced erections were completely suppressed by 1 μg SHU‐9119 i.c.v. Yawning was observed with i.c.v. and i.v. MT‐II, whereas spinal injection did not produce this behavior. SHU‐9119 blocked the erectile responses to i.th. MT‐II when injected i.th. but not i.c.v. Intracavernosal MT‐II neither increased intracorporal pressure nor augmented neurostimulated erectile responses. The lumbosacral spinal cord contains MC receptors that can initiate penile erection independent of higher centers. We confirmed the supraspinal proerectile action of MT‐II. These results provide insight into the central melanocortinergic pathways that mediate penile erection and may allow for more efficacious melanotropin‐based therapy for erectile dysfunction.

Exploring the Stereostructural Requirements of Peptide Ligands for the Melanocortin Receptors

Abstract: The melanotropin peptides α‐MSH, γ‐MSH, and β‐MSH are believed to be the natural ligands for the four melanocortin receptors, MC1R, MC3R, MC4R, and MC5R. However, these peptides generally have low selectivity for these receptors. We report on some approaches to the development of selective agonists and antagonists peptide ligands for these receptors.

Synthesis of (2S,3S)-β-methyltryptophan

Nα-Fmoc-protected (2S,3S)-β-methyltryptophan has been synthesized by asymmetric synthesis through the aid of an oxazolidinone auxiliary. Coupling of the mixed anhydride of Nin-Boc-protected indoleacrylic acid to the oxazolidinone auxiliary was achieved by lithium bromide and N,N-dimethylpyridine (DMAP). This reaction is milder and more convenient to run than the traditional conditions using butyl lithium.

Design and bioactivities of melanotropic peptide agonists and antagonists: Design based on a conformationally constrained somatostatin template

α-Melanotropin and ACTH, POMC peptides, initiate biological activity by interaction with the classical pigment cell (α-MSH receptor, MC1R) and adrenal gland (ACTH receptor, MC2R) melanocortin receptors, respectively. The recently discovered MC3R, MC4R and MC5R receptors provide new targets and new biological functions for POMC peptides. We have developed conformationally constrained α-melanotropin peptides that interact with all of these receptors as agonists and antagonists and are examining new approaches to obtain highly selective ligands for each of these melanocortin receptors. Previously, we had converted somatostatin-derived peptides into potent and highly selective analogues that act as antagonists at the μ opioid receptors. Using the reverse turn template that came out of these studies, we have designed, de novo, agonist and antagonist peptide analogues that interact with melanocortin receptors.

A study of conjugate addition to a γ,δ-dioxolanyl-α,β-unsaturated ester

Abstract Diastereoselective phenylcuprate addition to (S)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-trans-2-propenoate has been achieved in the presence of lithium bromide, copper(I) cyanide, trimethylsilyl chloride and dimethylsulfide cocatalysts.

The Development of a Novel Highly Selective and Potent Agonist for Human Melanocortin 4 Receptor

α-, β-, and γ-MSH, along with adrenocorticotropic hormones form a group of endogenous neuropeptides that regulate several key biological functions via five melanocortin (MC1R-MC5R) seven transmembrane G-protein coupled receptors (GPCR). Recent studies have indicated that in humans, the MC4R plays an important role in controlling feeding behavior and energy homeostasis [1,2]. These studies have further shown that agonists at hMC4R promote a feeling of satiety, while antagonists induce feeding. Thus selective agonists at this receptor could find therapeutic applications as anti-obesity drugs. This work discusses the development of the first highly selective and potent agonist MK-1 (c[(O)C-CH2-CH2-C(O)-His6-D-Phe7-Arg8-Trp9-Lys10]-NH2), at the human MC4 receptor versus the other three hMCR’s (hMC1, hMC3 and hMC5) respectively.

Diisopropylethylamine salts for protected amino acids: Direct synthesis of peptides on solid-phase

The use of highly hydrophilic amino acids, such as -methyl-histidine [( -Me)His], in peptide synthesis is challenging due to difficulties in the preparation of the pure -Boc protected derivatives. Although it has been reported [1] that Boc-( -Me)His could be extracted into organic solvents from water, we have not been able to repeat this procedure. Thus, we have pursued new approaches, such as by using the Boc-( -Me)His DIEA salt mixed with the HC1 salt of DIEA, to overcome such problems during the synthesis of MSH analogs.