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Varro E. Tyler Distinguished Lectureship 2013 Abstracts

Speaker: Dr. Philip S. Portoghese, PhD

Lecture Title:
Targeting Putative MOR-mGluR5 Heteromer in the Design of Highly Effective Analgesics for Treatment of Pain Arising from Tissue or Nerve Damage

Ordinarily, opioid analgesics are effective in treating pain caused by stimulation of peripheral nerve fibers. However, with pain in the presence of inflammation due to tissue damage (inflammatory pain) or to damage of the nervous system (neuropathic pain), opioids have lower efficacy. Upregulated glutamate and proinflammatory chemokines have been implicated in lowering the pain threshold under these conditions. Given the colocalization of mu opioid receptors (MOR) and metabotropic glutamate-5 receptors (GluR5) in glia, together with a report that they form a heteromer (MOR-mGluR5) in cultured cells, suggested the possibility that a putative heteromer could be a viable target in vivo.  Targeting this heteromer was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid receptor agonist and mGluR5 antagonist pharmacophores linked through spacers of varying length (10-24 atoms). When the series was evaluated for antinociception in inflamed mice, it was found that bivalent ligand MMG22 with a 22-atom spacer had unprecedented potency (i.t. ED50 ~9 fmol/mouse}. Members of the series with shorter or longer spacers were substantially less potent. The exceptional potency of MMG22 and the SAR of the series are consistent with optimal bridging of protomers in a putative MOR-mGluR5 heteromer. The finding that MMG22 possesses >106 therapeutic ratio suggests it is an excellent candidate for treatment of chronic, intractable pain via spinal administration.

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