Abstract
Melanocortins, peptides of the family of adrenocorticotropic (ACTH) and melanocyte-stimulating (MSH) hormones, have a wide range of physiological activity. Heptapeptide semax (MEHFPGP) is an analog of the ACTH4–10 fragment. Previously, pronounced nootropic and neuroprotective activities were shown for this peptide; in addition, it decreases pain sensitivity in animals. In this work, the relationship between analgesic activity of the peptide and its structure was studied. The following analogs of the N-terminal ACTH fragments were used: rMEHFPGP, where r is glucuronic acid, KEHFPGP, GEHFPGP, EHFPGP, HFPGP, and ERP. The peptides were administered intraperitoneally at doses of 0.015, 0.05 and 0.5 mg/kg. Rat pain sensitivity was assessed using the paw-withdrawal test. Truncations of the N-terminal residues eliminated the analgesic activity. The peptide analgesic effect was observed after the replacement of the N-terminal methionine with lysine or after the attachment of glucuronic acid to the methionine, while the peptide with glycine instead of the methionine had no effect on pain sensitivity. Hence, the amino acid at position 1 of semax analogs plays a key role in mediating the analgesic effects of the peptides.
Similar content being viewed by others
References
Alonso, M., Vianna, M.R., and Depino, A.M., Mello E Souza T., Pereira P., Szapiro G., Viola H., Pitossi F., Izquierdo I., Medina J.H. BDNF-Triggered Events in the Rat Hippocampus Are Required for Both Short-and Long-Term Memory Formation, Hippocampus, 2002, vol. 12, no. 4, pp. 551–560.
Ashmarin, I.P., Levitskaya, N.G., Antonova, L.V., Nezavibatko, V.N., Alfeeva, L.Yu., Dubinin, V.A., Golubobich, V.P., Ponomareva-Stepnaya, M.A., and Kamensky, A.A., The Neurotropic Activity of a Structural Analog of ACTH(5–7), Regulatory Peptides, 1994, vol. 51, p. 49–54.
Ashmarin, I.P., Nezavibatko, V.N., Levitskaya, N.G., Koshelev, V.B., and Kamensky, A.A., Disign and Investigation of An ACTH4–10 Analogue Lacking D-Amino Acids and Hydrophobic Radicals, Neurosci. Res. Commun., 1995, vol. 16, no. 2, pp. 105–112.
Ashmarin, I.P., Nezavibat’ko, V.N., Myasoedov, N.F., Kamenskii, A.A., Grivennikov, I.A., Ponomareva-Stepnaya, M.A., Andreeva, L.A., Kaplan, A.Ya., Koshelev, V.B., and Ryasina, T.V., Nootropnyi analog adrenokortikotropina 4–10 semaks (15-letnii opyt razrabotki i izucheniya), Zh. Vyssh. Nervn. Deyat., 1997, vol. 47, pp. 426–436.
De Wied, D., Witter, A., and Greven, H.M., Commentary: Behaviourally Active ACTH Analogues, Biochem. Pharmacol., 1975, vol. 24, pp. 1463–1468.
Dolotov, O.V., Seredenina, T.S., Levitskaya, N.G., Kamenskii, A.A., Andreva, L.A., Alfeeva, L.Yu., Nagaev, I.Yu., Zolotarev, Yu.A., Grivennikov, I.A., Engele, Yu., and Myasoedov, N.F., The Heptapeptide SEMAX stimulates BDNF Expression in Different Areas of the Rat Brain in vivo, Dokl. Akad. Nauk, 2003, vol. 391, no. 1, pp. 131–134.
Eremin, K.O., Kudrin, V.S., Grivennikov, I.A., Myasoedov, N.F., and Raevskii, K.S., Effects of Semax on Dopaminergic and Serotoninergic Systems of the Brain, Dokl. Akad. Nauk, 2004, vol. 394, no. 1, pp. 1–3.
Glazova, N.Yu., Levitskaya, N.G., Andreeva, L.A., Kamenskii, A.A., and Myasoedov, N.F., Nootropnye effekty novogo analoga fragmenta AKTG5–10-geksapeptida AKTG5-7-PGP (Nootropic Effects of the Hexapeptide ACTH5–7-PGP, a Novel Analog of the ACTH5–10 Fragment), Dokl. Akad. Nauk, 1999, vol. 367, no. 1, pp. 137–140.
Glazova, N.Yu., Sebentsova, E.A., Levitskaya, N.G., Andreeva, L.A., Alfeeva, L.Yu., Kamenskii, A.A., and Myasoedov, N.F., Effect of Modification of the N-Terminal Region of Semax on the Expression of Nootropic Effect of Semax Analogs, Izv. Akad. Nauk, Ser. Biol., 2005, no. 4, pp. 460–466.
Greven, H.M. and De Wied, D., Influence of Peptides Structurally Related to ACTH and MSH on Active Avoidance in Rats, Frontiers Hormone Res., 1977, vol. 4, pp. 140–152.
Ivanova, D.M., Levitskaya, N.G., Andreeva, L.A., Alfeeva, L.Yu., Kamenskii, A.A., and Myasoedov, N.F., The Effect of Semax on Animal Pain Sensitivity in Various Experimental Models, Dokl. Akad. Nauk, 2003, vol. 388, no. 3, pp. 416–419.
Kaplan, A.Ya., Koshelev, V.B., Nezavibat’ko, V.N., and Ashmarin, I.P., Increased Resistance to Hypoxia Effected by the Neuropeptide Preparation SEMAX, Fiziol. Chel., 1992, vol. 18, no. 5, pp. 104–107.
Klusa, V., Germane, S., Svirskis, S., and Wikberg, J.E., The Gamma(2)-MSH Peptide Mediates a Central Analgesic Effect via a GABA-ergic Mechanism That Is Independent from Activation of Melanocortin Receptors, Neuropeptides, 2001, vol. 35, no. 1, pp. 50–57.
Koroleva, M.V., Meizerov, E.E., Nezavibat’ko, V.N., Kamenskii, A.A., Dubynin, V.A., and Yakovlev, Yu.B., Study of the Analgesic Effect of the Semax Preparation, Byull. Eksp. Biol. Med., 1996, vol. 122, no. 11, pp. 527–529.
Kost, N.V., Sokolov, O.Yu., Gabaeva, M.V., Grivennikov, I.A., Andreeva, L.A., Myasoedov, N.F., and Zozulya, A.A., Semax and Selank Inhibit the Enkephalin-Degrading Enzymes from Human Serum, Bioorg. Khim., 2001, vol. 27, no. 3, pp. 180–183.
Levitskaya, N.G., Sebentsova, E.A., Glazova, N.Yu., Voskresenskaya, O.G., Andreeva, L.A., Alfeeva, L.Yu., Kamenskii, A.A., and Myasoedov, N.F., Issledovanie neirotropnoi aktivnosti produktov fermentativnoi degradatsii semaksa, Dokl. Akad. Nauk, 2000, vol. 372, no. 2, pp. 268–271.
Levitskaya, N.G., Sebentsova, E.A., Andreeva, L.A., Alfeeva, L.Yu., Kamenskii, A.A., and Myasoedov, N.F., Neuroprotective Effects of Semax in MPTP-Induced Disturbances of Brain Dopamine System, Ross. Fiziol. Zh. Im. Sechenova, 2002, vol. 88, no. 11, pp. 1369–1377.
Li, X.C., Li, H.D., and Zhao, B.Y., Serotonin of Hippocampus and Hypothalamus Taking Part in the Analgesic Effect of Adrenocorticotropic Hormone in Rats, Zhongguo Yao Li Xue Bao, 1990, vol. 11, no. 1, pp. 89–92.
South, S.M. and Smith, M.T., Apparent Insensitivity of the Hotplate Latency Test for Detection of Antinociception Following Intraperitoneal, Intravenous or Intracerebroventricular M6G Administration to Rats, J. Pharmacol. Exp. Ther., 1998, vol. 286, no. 3, pp. C. 1326–1332.
Starowicz, K. and Przewlocka, B., The Role of Melanocortins and Their Receptors in Inflammatory Processes, Nerve Regeneration and Nociception, Life Sci., 2003, vol. 73, no. 7, pp. 823–847.
Strand, F.L., New Vistas for Melanocortins. Finally, An Explanation for Their Pleiotropic Functions, Ann. New York Acad. Sci., 1999, vol. 897, pp. 1–16.
Takeshige, C., Tsuchiya, M., Zhao, W., and Guo, S., Analgesia Produced by Pituitary ACTH and Dopaminergic Transmission in the Arcuate, Brain Res. Bull., 1991, vol. 26, pp. 779–788.
Walker, J.M., Berntson, G.G., Sandman, C.A., Kastin, A.G., and Akil, H., Induction of Analgesia by Central Administration of ORG 2766, An Analog of ACTH 4-9, Eur. J. Pharmacol., 1981, vol. 69, pp. 71–79.
Wikberg, J.E.C., Muceniece, R., Mandrika, I., Prusis, P., Lindblom, J., Post, C., and Skottner, A., New Aspects on the Melanocortins and Their Receptors, Pharmacol. Res., 2000, vol. 42, no. 5, pp. 393–420.
Author information
Authors and Affiliations
Additional information
Original Russian Text © D.M. Ivanova, D.A. Vilenskii, N.G. Levitskaya, L.A. Andreeva, L.Yu. Alfeeva, A.A. Kamenskii, N.F. Myasoedov, 2006, published in Izvestiya Akademii Nauk, Seriya Biologicheskaya, 2006, No. 2, pp. 204–210.
Rights and permissions
About this article
Cite this article
Ivanova, D.M., Vilenskii, D.A., Levitskaya, N.G. et al. Study of the relationship between analgesic activity and structure of synthetic melanocortin analogs. Biol Bull Russ Acad Sci 33, 162–166 (2006). https://doi.org/10.1134/S1062359006020105
Received:
Issue Date:
DOI: https://doi.org/10.1134/S1062359006020105