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Design and synthesis of trivalent ligands targeting opioid, cholecystokinin, and melanocortin receptors for the treatment of pain

โœ Scribed by Yeon Sun Lee; Steve Fernandes; Vinod Kulkarani; Alexander Mayorov; Peg Davis; Shou-wu Ma; Kathy Brown; Robert J. Gillies; Josephine Lai; Frank Porreca; Victor J. Hruby

Publisher
Elsevier Science
Year
2010
Tongue
English
Weight
511 KB
Volume
20
Category
Article
ISSN
0960-894X

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โœฆ Synopsis

It has been known that co-administration of morphine with either cholecystokinin (CCK) receptor or melanocortin (MC) receptor antagonists enhance morphine's analgesic efficacy by reducing serious side effects such as tolerance and addiction. Considering these synergistic effects, we have designed trivalent ligands in which all three different pharmacophores for opioid, CCK, and MC receptors are combined in such a way as to conserve their own topographical pharmacophore structures. These ligands, excluding the cyclic compound, were synthesized by solid phase synthesis using Rink-amide resin under microwave assistance in very high yields. These trivalent ligands bind to their respective receptors well demonstrating that the topographical pharmacophore structures for the three receptors were retained for receptor binding. Ligand 10 was a lead compound to show the best biological activities at all three receptors.

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