The Joy of Melanocortin Receptors

Lose Weight and Improve Your Sex Life!

Those two pitches account for approximately 95% of all spam, right? But what if you could manufacture one drug that promises to do both things? Think of the profits!!

Although it sounds too good to be true, there may yet be such a substance: drugs acting as agonists at the melanocortin 4 receptor (MC4-R). A recent article in Neuron focused on the weight loss aspects of MC4-R. Serotonergic agents were administered to obese and regular mice; both groups reduced their food intake as a result. The figure above illustrates how serotonin is thought to act on melanocortin pathways (via actions at the serotonin 1B receptor, 5-HT1BR).

Detailed explanation [Figure 8 of Heisler et al.]: 5-HT hyperpolarizes and inhibits AgRP neurons and decreases an inhibitory drive onto POMC cells by activation of 5-HT1BRs. 5-HT also activates POMC neurons via activation of 5-HT2CRs. This leads to reciprocal increases in a-MSH release and decreases in AgRP release at MC4-R in target sites.

Translated, the arcuate nucleus of the hypothalamus may play a central role in appetite suppression. The arcuate has two populatons of neurons: one expressing the anorectic melanocortin receptor agonist, a-MSH (green neuron) and the other expressing the appetitite-stimulating melanocortin receptor antagonist, AgRP (blue neuron). The combined increase in a-MSH and decrease in AgRP act at downstream MC4 receptors to suppress appetitite.

Heisler LK, Jobst EE, Sutton GM, Zhou L, Borok E, Thornton-Jones Z, Liu HY, Zigman JM, Balthasar N, Kishi T, Lee CE, Aschkenasi CJ, Zhang CY, Yu J, Boss O, Mountjoy KG, Clifton PG, Lowell BB, Friedman JM, Horvath T, Butler AA, Elmquist JK, Cowley MA. (2006). Serotonin Reciprocally Regulates Melanocortin Neurons to Modulate Food Intake. Neuron 51:239-249.

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT(1B)Rs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.

However, the serotonergic drugs given to the mice in that study included D-fenfluramine, part of the scary and dangerous fen-phen fiasco. Fen-phen was linked to heart valve disease and pulmonary hypertension, and was withdrawn from the U.S. market in 1997. The mice were also given an experimental 5-HT1BR agonist not yet approved for human use.

Are there any drugs that act directly at MC4-R? And what about sexual function? Where is that miracle aphrodisiac weight loss supplement you promised??

In contrast to the modest weight loss associated with short-term SSRI treatment, these antidepressant drugs are associated with high rates of sexual side effects. Enter PT-141.

Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB. (2004). Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res. 16:51-9.

Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. (2004). Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res. 16:135-42.

Diamond LE, Earle DC, Heiman JR, Rosen RC, Perelman MA, Harning R. (2006). An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med. 3:628-38.

Back in April, there was an article in The Observer Magazine and a post in Pharyngula about this compound. A good place to start if you really want to learn about MC4-R agonists is this article:

Nargund RP, Strack AM, Fong TM. (2006). Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J Med Chem. 49:4035-43.

Funniest lines from the article:

If MC4R agonists induce spontaneous penile erections in men, this would represent a significant impediment to the development of compounds to treat obesity.

The nonselective melanocortin agonists, 1 and 3, have nausea and vomiting as adverse side effects when administered to humans either subcutaneously or intranasally. Attempts to study whether the effects of these two structurally related molecules are mechanism-based have been of limited utility.

Is PT-141 really a miracle drug? That's highly doubtful. But, as PZ Myers said,

Wow. Makes me want to run out and buy stock in Palatin Technologies, the manufacturer.