Bhat, Pritesh and Mor, Vijay and Pai, KSR and Chowdary, PVR (2012) Pharmacophore Modeling of Delta And Mu Receptors And Synthesis of Enkephalines With D-[LEU] 5C-Terminal Modifications Delta Selective Agonists. International Journal Of Pharmacy&Technology, 4 (2). pp. 4350-4391.

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Abstract

Opioid analgesics are most commonly used analgesics in the treatment of chronic and severe pain. However these opioid analgesic compounds pose side effects such as respiratory depression psychological dependence etc. δ agonistic activity is associated with analgesic activity where as μ agonistic activity is associated with side effects. Hence, the aim in research community is to develop selective δ receptor agonists. In this study, ligand based 3D pharmacophore model was developed for δ and μ opioid receptor. A virtual screening protocol was used to identify high δ selective agonists from a database of about 300,000 compounds from which δ receptor agonists were identified. The hits obtained were further screened for μ receptor model and the common hits were discarded. The virtual screening of data base identified the enkephalin-D-Leu peptidomimetics analogues to be highly δ selective agonist. The penta peptide agonists were synthesized by solid phase peptide synthesis and tested for δ and μ receptor agonistic activity by mouse vas deference (MVD) and guinea pig ileum (GPI) bioassay. The hits identified were highly selective to the δ opioid receptor with a selectivity ratio of 3,500 to 15,000. These compounds have exhibited a significant analgesic in-vivo activity in hot plate and acetic acid writhing models, had no effect on locomotor activity. We hypothesize that, a ligand satisfying hydrophobic feature and hydrogen bond donor at address part will have high δ opioid receptor agonistic activity whereas ligands having hydrogen bond acceptor will bind preferentially to μ opioid receptor

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