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Melanocyte-inhibiting factor chemical structure
Melanocyte-inhibiting factor

IUPAC name
CAS number
ATC code


Chemical formula {{{chemical_formula}}}
Molecular weight 284.355 g/mol
Bioavailability 100% (injected)
Metabolism plasma protease enzymes
Elimination half-life
Excretion N/A
Pregnancy category
Legal status
Routes of administration IV

Melanocyte-inhibiting factor (also known as Pro-Leu-Gly-NH2, Melanostatin, MSH release-inhibiting hormone or MIF-1) is an endogenous peptide fragment derived from cleavage of the hormone oxytocin, but having generally different actions in the body.[1][2] MIF-1 produces multiple effects, both blocking the effects of opioid receptor activation,[3][4][5][6][7][8] while at the same time acting as a positive allosteric modulator of the D2 and D4 dopamine receptor subtypes,[9][10][11][12][13][14][15][16][17] as well as inhibiting release of other neuropeptides such as alpha-MSH,[18][19][20] and potentiating melatonin activity.[21]

This complex mix of actions produces a profile of antidepressant,[22][23][24] nootropic,[25][26][27][28] and anti-Parkinsonian effects when MIF-1 is administered,[29][30][31] and it has been investigated for various medical uses. MIF-1 is unusually resistant to metabolism in the bloodstream,[32] and crosses the blood–brain barrier easily,[33][34] though it is poorly active orally and is usually injected. Several other closely related peptides with important actions in the body include Tyr-MIF-1 and endomorphin-1 and -2.[35][36][37][38][39]

See alsoEdit


  1. Celis ME, Taleisnik S, Walter R (July 1971). Regulation of formation and proposed structure of the factor inhibiting the release of melanocyte-stimulating hormone. Proceedings of the National Academy of Sciences of the United States of America 68 (7): 1428–33.
  2. Petersson M, Uvnäs-Moberg K (December 2004). Prolyl-leucyl-glycinamide shares some effects with oxytocin but decreases oxytocin levels. Physiology & Behavior 83 (3): 475–81.
  3. Chiu S, Mishra RK (January 1979). Antagonism of morphine-induced catalepsy by L-prolyl-L-leucyl-glycinamide. European Journal of Pharmacology 53 (2): 119–25.
  4. Dickinson SL, Slater P (1980). Opiate receptor antagonism by L-prolyl-L-leucyl-glycinamide, MIF-I. Peptides 1 (4): 293–9.
  5. Contreras PC, Takemori AE (June 1984). Effect of prolyl-leucyl-glycinamide and alpha-melanocyte-stimulating hormone on levorphanol-induced analgesia, tolerance and dependence. Life Sciences 34 (26): 2559–66.
  6. Ehrensing RH, Kastin AJ, Michell GF (December 1984). Antagonism of morphine analgesia by prolyl-leucyl-glycinamide (MIF-1) in humans. Pharmacology, Biochemistry, and Behavior 21 (6): 975–8.
  7. Galina ZH, Kastin AJ (December 1986). Existence of antiopiate systems as illustrated by MIF-1/Tyr-MIF-1. Life Sciences 39 (23): 2153–9.
  8. Bocheva A, Dzambazova-Maximova E (November 2004). Antiopioid properties of the TYR-MIF-1 family. Methods and Findings in Experimental and Clinical Pharmacology 26 (9): 673–7.
  9. Kostrzewa RM, Spirtes MA, Klara JW, Christensen CW, Kastin AJ, Joh TH (1976). Effects of L-prolyl-L-leucyl-glycine amide (MIF-I) on dopaminergic neurons. Pharmacology, Biochemistry, and Behavior 5 (Suppl 1): 125–7.
  10. Singhal RL, Rastogi RB (February 1982). MIF-1: effects on norepinephrine, dopamine and serotonin metabolism in certain discrete brain regions. Pharmacology, Biochemistry, and Behavior 16 (2): 229–33.
  11. Chiu P, Rajakumar G, Chiu S, Johnson RL, Mishra RK (1985). Mesolimbic and striatal dopamine receptor supersensitivity: prophylactic and reversal effects of L-prolyl-L-leucyl-glycinamide (PLG). Peptides 6 (2): 179–83.
  12. Xu DL, Yu WC, Pan GB, Chen SD (1987). Mechanism of action of L-leucyl-glycinamide and its effect on Parkinson's disease. Advances in Neurology 45: 587–90.
  13. Verma V, Mann A, Costain W, Pontoriero G, Castellano JM, Skoblenick K, Gupta SK, Pristupa Z, Niznik HB, Johnson RL, Nair VD, Mishra RK (December 2005). Modulation of agonist binding to human dopamine receptor subtypes by L-prolyl-L-leucyl-glycinamide and a peptidomimetic analog. The Journal of Pharmacology and Experimental Therapeutics 315 (3): 1228–36.
  14. Fisher A, Mann A, Verma V, Thomas N, Mishra RK, Johnson RL (January 2006). Design and synthesis of photoaffinity-labeling ligands of the L-prolyl-L-leucylglycinamide binding site involved in the allosteric modulation of the dopamine receptor. Journal of Medicinal Chemistry 49 (1): 307–17.
  15. Vartak AP, Skoblenick K, Thomas N, Mishra RK, Johnson RL (December 2007). Allosteric modulation of the dopamine receptor by conformationally constrained type VI beta-turn peptidomimetics of Pro-Leu-Gly-NH2. Journal of Medicinal Chemistry 50 (26): 6725–9.
  16. Raghavan B, Skoblenick KJ, Bhagwanth S, Argintaru N, Mishra RK, Johnson RL (April 2009). Allosteric modulation of the dopamine D2 receptor by Pro-Leu-Gly-NH2 peptidomimetics constrained in either a polyproline II helix or a type II beta-turn conformation. Journal of Medicinal Chemistry 52 (7): 2043–51.
  17. Mann A, Verma V, Basu D, Skoblenick KJ, Beyaert MG, Fisher A, Thomas N, Johnson RL, Mishra RK (September 2010). Specific binding of photoaffinity-labeling peptidomimetics of Pro-Leu-Gly-NH2 to the dopamine D2L receptor: evidence for the allosteric modulation of the dopamine receptor. European Journal of Pharmacology 641 (2-3): 96–101.
  18. Scimonelli T, Celis ME (1982). Inhibition by L-prolyl-L-leucyl-glycinamide (PLG) of alpha-melanocyte stimulating hormone release from hypothalamic slices. Peptides 3 (6): 885–9.
  19. McCullen RK, Peiffer RL, Jennes L, Hernandez DE (1988). Inhibition by MIF-I of alpha-MSH induced increase of intraocular pressure and miosis in rabbits. Neuropeptides 12 (4): 213–7.
  20. Caballero C, Celis ME (May 1993). The effect of the blockade of alpha-melanocyte-stimulating hormone on LH release in the rat. The Journal of Endocrinology 137 (2): 197–202.
  21. Sandyk R (May 1990). MIF-induced augmentation of melatonin functions: possible relevance to mechanisms of action of MIF-1 in movement disorders. The International Journal of Neuroscience 52 (1-2): 59–65.
  22. Pignatiello MF, Olson GA, Kastin AJ, Ehrensing RH, McLean JH, Olson RD (March 1989). MIF-1 is active in a chronic stress animal model of depression. Pharmacology, Biochemistry, and Behavior 32 (3): 737–42.
  23. Kostowski W, Danysz W, Dyr W, Jankowska E, Krzaścik P, Pałejko W, Stefański R, Płaźnik A (1991). MIF-1 potentiates the action of tricyclic antidepressants in an animal model of depression. Peptides 12 (5): 915–8.
  24. Ehrensing RH, Kastin AJ, Wurzlow GF, Michell GF, Mebane AH (August 1994). Improvement in major depression after low subcutaneous doses of MIF-1. Journal of Affective Disorders 31 (4): 227–33.
  25. Stratton LO, Kastin AJ (1975). Increased acquisition of a complex appetitive task after MSH and MIF. Pharmacology, Biochemistry, and Behavior 3 (5): 901–4.
  26. Davis JL, Pico RM, Cherkin A (November 1982). Memory enhancement induced in chicks by L-prolyl-L-leucyl-glycinamide. Pharmacology, Biochemistry, and Behavior 17 (5): 893–6.
  27. d'Amore A, Pieretti S, Palazzesi S, Pezzini G, Chiarotti F, Scorza T, Loizzo A (1990). MIF-1 can accelerate neuromotor, EEG and behavioral development in mice. Peptides 11 (3): 527–32.
  28. Khan RS, Yu C, Kastin AJ, He Y, Ehrensing RH, Hsuchou H, Stone KP, Pan W (2010). Brain Activation by Peptide Pro-Leu-Gly-NH(2) (MIF-1). International Journal of Peptides 2010.
  29. Kastin AJ, Ehrensing RH, Olson RD, Coy DH (1980). Neurological effects of MIF-1, MSH, and opiate peptides in clinical studies. International Journal of Neurology 14 (2-4): 205–9.
  30. Katzenschlager R, Jackson MJ, Rose S, Stockwell K, Tayarani-Binazir KA, Zubair M, Smith LA, Jenner P, Lees AJ (April 2007). Antiparkinsonian activity of L-propyl-L-leucyl-glycinamide or melanocyte-inhibiting factor in MPTP-treated common marmosets. Movement Disorders : Official Journal of the Movement Disorder Society 22 (5): 715–9.
  31. Castellano JM, Batrynchuk J, Dolbeare K, Verma V, Mann A, Skoblenick KJ, Johnson RL, Mishra RK (October 2007). MIF-1 and its peptidomimetic analogs attenuate haloperidol-induced vacuous chewing movements and modulate apomorphine-induced rotational behavior in 6-hydroxydopamine-lesioned rats. Peptides 28 (10): 2009–15.
  32. Kastin AJ, Hahn K, Erchegyi J, Zadina JE, Hackler L, Palmgren M, Banks WA (February 1994). Differential metabolism of Tyr-MIF-1 and MIF-1 in rat and human plasma. Biochemical Pharmacology 47 (4): 699–709.
  33. Reed GW, Olson GA, Olson RD (1994). The Tyr-MIF-1 family of peptides. Neuroscience and Biobehavioral Reviews 18 (4): 519–25.
  34. Banks WA, Kastin AJ (January 1994). Opposite direction of transport across the blood–brain barrier for Tyr-MIF-1 and MIF-1: comparison with morphine. Peptides 15 (1): 23–9.
  35. Kastin AJ, Hahn K, Zadina JE, Banks WA, Hackler L (April 1995). Melanocyte-stimulating hormone release-inhibiting factor-1 (MIF-1) can be formed from Tyr-MIF-1 in brain mitochondria but not in brain homogenate. Journal of Neurochemistry 64 (4): 1855–9.
  36. Zadina JE, Hackler L, Ge LJ, Kastin AJ (April 1997). A potent and selective endogenous agonist for the mu-opiate receptor. Nature 386 (6624): 499–502.
  37. Pan W, Kastin AJ (December 2007). From MIF-1 to endomorphin: the Tyr-MIF-1 family of peptides. Peptides 28 (12): 2411–34.
  38. Rotzinger S, Lovejoy DA, Tan LA (April 2010). Behavioral effects of neuropeptides in rodent models of depression and anxiety. Peptides 31 (4): 736–56.
  39. Dyck B, Guest K, Sookram C, Basu D, Johnson R, Mishra RK (January 2011). PAOPA, a potent analogue of Pro-Leu-glycinamide and allosteric modulator of the dopamine D2 receptor, prevents NMDA receptor antagonist (MK-801)-induced deficits in social interaction in the rat: implications for the treatment of negative symptoms in schizophrenia. Schizophrenia Research 125 (1): 88–92.

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