Melanocortins and the brain: from effects via receptors to drug targets

Melanocortins and the brain: from effects via receptors to drug targets The lack of specific receptors (and antagonists) has hampered the research on the neural mechanism of action of adrenocorticotropic hormone (ACTH)- and melanocyte-stimulating hormone (MSH)-like peptides. Yet the original observations in the 1970s already pointed to cAMP as a possible mediator of ACTH/MSH effects in neurons. The cloning of melanocortin receptors since 1992, the identification of at least two subtypes (melanocortin MC 3 and MC 4 receptors) that are present in neural tissue and the development of selective and potent agonists as well as antagonists have markedly furthered the position of melanocortins as important neuropeptides. In this paper we discuss the role of especially the receptor subtype melanocortin MC 4 in various behaviors including grooming behavior and feeding behavior and consider new insights in the interaction between the opioid and the melanocortin system at the level of the spinal cord (i.e. pain perception). Finally, based on new data obtained in molecular pharmacological studies on brain melanocortin receptors, we suggest a general concept for selective receptor–ligand interaction: ligand residues outside the peptide core-sequence may direct the conformation of the residues in the ligand core-sequence that interact directly with the receptor-binding pocket and thereby determine selectivity. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Pharmacology Elsevier

Melanocortins and the brain: from effects via receptors to drug targets

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Publisher
Elsevier
Copyright
Copyright © 2000 Elsevier Science B.V.
ISSN
0014-2999
DOI
10.1016/S0014-2999(00)00537-9
Publisher site
See Article on Publisher Site

Abstract

The lack of specific receptors (and antagonists) has hampered the research on the neural mechanism of action of adrenocorticotropic hormone (ACTH)- and melanocyte-stimulating hormone (MSH)-like peptides. Yet the original observations in the 1970s already pointed to cAMP as a possible mediator of ACTH/MSH effects in neurons. The cloning of melanocortin receptors since 1992, the identification of at least two subtypes (melanocortin MC 3 and MC 4 receptors) that are present in neural tissue and the development of selective and potent agonists as well as antagonists have markedly furthered the position of melanocortins as important neuropeptides. In this paper we discuss the role of especially the receptor subtype melanocortin MC 4 in various behaviors including grooming behavior and feeding behavior and consider new insights in the interaction between the opioid and the melanocortin system at the level of the spinal cord (i.e. pain perception). Finally, based on new data obtained in molecular pharmacological studies on brain melanocortin receptors, we suggest a general concept for selective receptor–ligand interaction: ligand residues outside the peptide core-sequence may direct the conformation of the residues in the ligand core-sequence that interact directly with the receptor-binding pocket and thereby determine selectivity.

Journal

European Journal of PharmacologyElsevier

Published: Sep 29, 2000

References

  • Effects of ACTH on seizure susceptibility in the developing brain
    Holmes, G.L.; Weber, D.A.
  • B-50, the growth associated protein-43: modulation of cell morphology and communication in the nervous system
    Oestreicher, A.B.; de Graan, P.N.; Gispen, W.H.; Verhaagen, J.; Schrama, L.H.
  • Discovery of novel melanocortin-4 receptor selective MSH analogues
    Schioth, H.B.; Mutulis, F.; Muceniece, R.; Prusis, P.; Wikberg, J.E.
  • Putative neurotrophic factors and functional recovery from peripheral nerve damage in the rat
    Van Der Zee, C.E.E.M.; Brakkee, J.H.; Gispen, W.H.
  • The role of central melanocortin receptors in the activation of the hypothalamus–pituitary–adrenal-axis and the induction of excessive grooming
    Von Frijtag, J.C.; Croiset, G.; Gispen, W.H.; Adan, R.A.; Wiegant, V.M.

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