A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

Abstract

Melanocortin receptors are considered promising candidates for the treatment of behavioral and metabolic disorders ranging from obesity to anorexia and cachexia. These experiments examined the response of mice to peripheral injections of two compounds. PG932 is a derivative of SHU9119 which is non-selective antagonist of melanocortin-3 and melanocortin-4 receptors (Mc3r, Mc4r). PG946 is a derivative of a hybrid of alpha-and beta-MSH, and is a moderately selective Mc3r antagonist. SHU9119 increases food intake when administered intracerebroventricularly but is without effect when injected into the periphery. In contrast, PG932 was found to be highly effective at stimulating food intake when administered peripherally by intraperitoneal injection. The orexigenic effect of PG932 required functional Mc4r, suggesting that inhibition of this receptor is involved in the stimulation of food intake. PG946 did not significantly affect on feeding behavior. PG932 is thus a useful new compound for studies examining the regulation of appetite and energy balance, and may also prove useful for the treatment of cachectic conditions.

Vector-Mediated Transport Producing Drug-like Peptides

“…In vivo structure:activity studies were modeled around an established anticachexia MC4R antagonist peptide that had apparent BBB transport activity; PG932 (Table 1). We noted that PG932's structure included two dipeptide features that differentiated it from an analogous MC4R antagonist peptide (SHU9119) that lacked BBB transport (Sutton et al, 2008). These included a proline (adjacent to an aromatic residue) within the cyclized region of the sequence, and a C-terminus composed of non-polar residues from the flanking region of α-MSH; Pro-Val (Eberle and Schwyzer, 1976).…”

“…The MC antagonist pharmacophore in TCMCB03 (His-D-Nal-Arg-Trp) is identical to that in SHU9119, an established MC4R antagonist. However, SHU9119 has no transport activity, requiring intracerebroventricular administration for use as an anticachexia agent (Sutton et al, 2008).…”

“…Reports that an occasional biologically active peptide under investigation had blood-brainbarrier (BBB) transport and/or oral activity for unexplained reasons are scattered throughout the medical research literature (Rodriguez et al, 1993, Sefler et al, 1995, Sutton et al, 2008, Hess et al, 2008. The few attempts to explore this mechanism (or mechanisms) of action have generally failed to define any specific structural features governing these activities, which could then be applied to peptides with potentially therapeutic activity to produce drug-like analogs.…”

Melanocortin-3 Receptors and Metabolic Homeostasis

“…54 ) and also an MC3/4R antagonist, stimulates food intake when administered peripherally, and that this action is dependent on MC4Rs. 191 Navarro et al observed what appeared to be a stimulatory effect of MTII administered icv. to Mc4r −/− mice, while the inhibitory effects of peripherally administered MTII were retained.…”

The role of melanocortin neuronal pathways in circadian biology: a new homeostatic output involving melanocortin‐3 receptors?

“…NPY/AgRP and Pomc/CART neurons may transmit signals of energy status into the DMH expressing melanocortin-3 receptor (Mc3r). Alternatively, neurons expressing Mc3r reside in other areas of the brain, such as the LHA and ventral tegmental area (102), involved in complex behavioural processes. An involvement of these neurons in the expression of rhythms in arousal and food-seeking behaviour is also possible.…”