Long term orexigenic effect of a novel melanocortin
4 receptor selective antagonist
- We designed and synthesized several novel cyclic
MSH analogues and tested their affinities for
cells expressing the MC1, MC3, MC4 and MC5 receptors.
- One of the substances HS028 (cyclic [AcCys11,
dichloro-D-phenylalanine14, Cys18, Asp-NH222]-ß-MSH11
- 22) showed high affinity (Ki of 0.95nM) and
high (80 fold) MC4 receptor selectivity over the
MC3 receptor. HS028 thus shows both higher affinity
and higher selectivity for the MC4 receptor compared
to the earlier first described MC4 receptor selective
substance HS014.
- HS028 antagonised a -MSH induced increase in
cyclic AMP production in transfected cells expressing
the MC3 and MC4 receptors, whereas it seemed to
be a partial agonist for the MC1 and MC5 receptors.
- Chronic intracerebroventricularly (i.c.v.)
administration of HS028 by osmotic minipumps significantly
increased both food intake and body weight in
a dose dependent manner without tachyphylaxis
for a period of 7 days.
- This is the first report demonstrating that
an MC4 receptor antagonist can increase food intake
and body weight during chronic administration
providing further evidence that the MC4 receptor
is an important mediator of long term weight homeostasis.
Skuladottir GV
et al. Br. J. Pharmacol., Jan 1999; 126: 27 - 34
Orexigenic effect of the melanocortin MC4 receptor
antagonist HS014 is inhibited only partially by neuropeptide
Y Y1 receptor selective antagonists
Neuropeptide Y (NPY) and melanocortin (MC) peptides
have opposite effects on food intake: NPY-like peptides
and MC receptor antagonists stimulate feeding and
increase body weight, whereas melanocortins and NPY
antagonists inhibit food intake. In this study we
tested whether the orexigenic effect of the selective
MC4 receptor antagonist HS014 (1 nmol) could be inhibited
by three different NPY antagonists, (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]D-argininam
ide (BIBP3226), (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2(diphenyl
acetyl)-argininamidetrifluoroacetate (BIBO3304), and
decapeptide [D-Tyr(27,36)D-Thr32]NPY(27-36), after
icv administration in freely feeding male rats. All
three NPY receptor antagonists inhibited the orexigenic
effects of HS014 partially and with markedly different
potency. [D-Tyr(27,36)D-Thr32]NPY(27-36) was active
only in subconvulsive dose. The NPY Y1 selective antagonist
BIBP3226 was more effective in inhibiting the effect
of HS014 than BIBO3304 despite in vitro data indicating
that BIBP3226 is about 10 times less potent than BIBO3304
at NPY Y1 receptor. An enantiomer of BIBO3304, BIBO3457,
failed to inhibit HS014-induced feeding, indicating
that the effects of BIBO3304 were stereoselective.
These results suggest that stimulation of food intake
caused by weakening of melanocortinergic tone at the
MC4 receptor is partially but not exclusively related
to NPY Y1 receptor activation.
Kask A, Schioth HB, Harro J,
Wikberg JE, Rago L. Can J Physiol Pharmacol 2000 Feb;78(2):143-9
Long-term administration of MC4 receptor antagonist
HS014 causes hyperphagia and obesity in rats
In this study we investigated the long term effects
of a potent and selective melanocortin 4 (MC4) receptor
antagonist (HS014) on food intake, body weight, body
composition and blood glucose levels in adult rats.
HS014 was injected i.c.v. either by twice-daily injections
(2 x 1 nmol) for 6 days or administered by continuous
infusion with osmotic minipumps (0.16 nmol/h) for
2 weeks. The results show a considerable increase
in food intake and body weight after both of the treatments
without any signs of tachyphylaxis. After 2 weeks
of treatment with osmotic pumps, the HS014-treated
rats (average weight 425g) had 20% higher body weight
than the controls rats (average 360 g). When i.c.v.
injections were terminated, the body weight of the
twice-daily HS014-treated rats returned to the levels
of control group, whereas the rats treated with continuous
infusion of HS014 remained hyperphagic and still gained
weight. Blood glucose levels in the rats treated with
HS014 infusion were significantly increased. Analysis
of body composition in HS014-infused rats indicated
that body weight was increased due to fat deposits.
These data show for the first time that chronic administration
of exogenous MC4 receptor antagonist causes hyperphagia
and severe obesity in rats. These data also indicate
that the melanocortic control of food intake is very
robust and suggest that changes induced by such treatment
overcome negative feedback signals.
Kask A, Pahkla R, Irs A, Rago
L, Wikberg JE, Schioth HB. Neuroreport 1999 Mar 17;10(4):707-11
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