Galmic, a nonpeptide galanin receptor agonist, affects behaviours in seizure, pain, and forced-swim tests

T. Barfai, X. lu, H. Badie-Mahdavi, A. M. Barr, A. Mazarati, X. Y. Hua, T. Yaksh, G. Haberhauser, S. C. Ceide, Laurent Alain Claude Trembleau, L. Somogyi, L. Krock, J. Rebek Jnr

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GaIR1 receptors (Ki = 34.2 muM) and virtually no affinity for GaIR2 receptors. In vitro, Galmic, like galanin, suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces.

Original languageEnglish
Pages (from-to)10470-10475
Number of pages5
JournalPNAS
Volume101
DOIs
Publication statusPublished - 2004

Keywords

  • MARINE NATURAL-PRODUCTS
  • STATUS EPILEPTICUS
  • ALPHA-HELIX
  • SUBTYPES
  • ANTICONVULSANT
  • IDENTIFICATION
  • ANTAGONIST
  • PEPTIDE
  • ANALOGS
  • MODEL

Cite this

Barfai, T., lu, X., Badie-Mahdavi, H., Barr, A. M., Mazarati, A., Hua, X. Y., ... Rebek Jnr, J. (2004). Galmic, a nonpeptide galanin receptor agonist, affects behaviours in seizure, pain, and forced-swim tests. PNAS, 101, 10470-10475. https://doi.org/10.1073/pnas.0403802101

Galmic, a nonpeptide galanin receptor agonist, affects behaviours in seizure, pain, and forced-swim tests. / Barfai, T.; lu, X.; Badie-Mahdavi, H.; Barr, A. M.; Mazarati, A.; Hua, X. Y.; Yaksh, T.; Haberhauser, G.; Ceide, S. C.; Trembleau, Laurent Alain Claude; Somogyi, L.; Krock, L.; Rebek Jnr, J.

In: PNAS, Vol. 101, 2004, p. 10470-10475.

Research output: Contribution to journalArticle

Barfai, T, lu, X, Badie-Mahdavi, H, Barr, AM, Mazarati, A, Hua, XY, Yaksh, T, Haberhauser, G, Ceide, SC, Trembleau, LAC, Somogyi, L, Krock, L & Rebek Jnr, J 2004, 'Galmic, a nonpeptide galanin receptor agonist, affects behaviours in seizure, pain, and forced-swim tests', PNAS, vol. 101, pp. 10470-10475. https://doi.org/10.1073/pnas.0403802101
Barfai, T. ; lu, X. ; Badie-Mahdavi, H. ; Barr, A. M. ; Mazarati, A. ; Hua, X. Y. ; Yaksh, T. ; Haberhauser, G. ; Ceide, S. C. ; Trembleau, Laurent Alain Claude ; Somogyi, L. ; Krock, L. ; Rebek Jnr, J. / Galmic, a nonpeptide galanin receptor agonist, affects behaviours in seizure, pain, and forced-swim tests. In: PNAS. 2004 ; Vol. 101. pp. 10470-10475.
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T1 - Galmic, a nonpeptide galanin receptor agonist, affects behaviours in seizure, pain, and forced-swim tests

AU - Barfai, T.

AU - lu, X.

AU - Badie-Mahdavi, H.

AU - Barr, A. M.

AU - Mazarati, A.

AU - Hua, X. Y.

AU - Yaksh, T.

AU - Haberhauser, G.

AU - Ceide, S. C.

AU - Trembleau, Laurent Alain Claude

AU - Somogyi, L.

AU - Krock, L.

AU - Rebek Jnr, J.

PY - 2004

Y1 - 2004

N2 - The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GaIR1 receptors (Ki = 34.2 muM) and virtually no affinity for GaIR2 receptors. In vitro, Galmic, like galanin, suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces.

AB - The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GaIR1 receptors (Ki = 34.2 muM) and virtually no affinity for GaIR2 receptors. In vitro, Galmic, like galanin, suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces.

KW - MARINE NATURAL-PRODUCTS

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KW - ALPHA-HELIX

KW - SUBTYPES

KW - ANTICONVULSANT

KW - IDENTIFICATION

KW - ANTAGONIST

KW - PEPTIDE

KW - ANALOGS

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