Design, Synthesis and Functional Analysis of Cyclic Opioid Peptides with Dmt-Tic Pharmacophore

The opioid receptors are members of the G-protein-coupled receptor (GPCR) family and are known to modulate a variety of biological functions, including pain perception. Despite considerable advances, the mechanisms by which opioid agonists and antagonists interact with their receptors and exert their effect are still not completely understood. In this report, six new hybrids of the Dmt-Tic pharmacophore and cyclic peptides, which were shown before to have a high affinity for the mu-opioid receptor (MOR) were synthesized and characterized pharmacologically in calcium mobilization functional assays. All obtained ligands turned out to be selective antagonists of the delta-opioid receptor (DOR) and did not activate or block the MOR. The three-dimensional structural determinants responsible for the DOR antagonist properties of these analogs were further investigated by docking studies. The results indicate that these compounds attach to the DOR in a slightly different orientation with respect to the Dmt-Tic pharmacophore than Dmt-Tic psi[CH2-NH]Phe-Phe-NH2 (DIPP-NH2[psi]), a prototypical DOR antagonist peptide. Key pharmacophoric contacts between the DOR and the ligands were maintained through an analogous spatial arrangement of pharmacophores, which could provide an explanation for the predicted high-affinity binding and the experimentally observed functional properties of the novel synthetic ligands

Drug Evolution Concept in Drug Design: 1. Hybridization Method\u2020

A novel concept, \u201cdrug evolution\u201d, is proposed to develop chemical libraries that have a high probability of finding drugs or drug candidates. It converts biological evolution into chemical evolution. In this paper, we present \u201chybridization\u201d drug evolution, which is the equivalent of sexual recombination of parental genomes in biological evolution. The hybridization essentially shuffles the building blocks of the parent drugs and ought to drug(s); no drug evolution can otherwise occur. We hybridized two drugs, benzocaine and metoclopramide and generated 16 molecules that include the parent drugs, four known drugs, and two molecules whose therapeutic activities are reported. The unusually high number of drugs and drug candidates in the library encourages high expectations of finding new drug(s) or drug candidate(s) within the remaining eight compounds. Interestingly, the therapeutic applications of the eight drugs or drug candidates in the library are fairly diverse as 38 therapeutic applications and 25 molecular targets are counted. Therefore, the library fits as a general chemical library for unspecified therapeutic activities. The hybridization of other two drugs, aspirin and cresotamide, is also described to demonstrate the generality of the method.NRC publication: Ye

Analgesic Peptides: From Natural Diversity to Rational Design

Pain affects one-third of the global population and is a significant public health issue. The use of opioid drugs, which are the strongest painkillers, is associated with several side effects, such as tolerance, addiction, overdose, and even death. An increasing demand for novel, safer analgesic agents is a driving force for exploring natural sources of bioactive peptides with antinociceptive activity. Since the G protein-coupled receptors (GPCRs) play a crucial role in pain modulation, the discovery of new peptide ligands for GPCRs is a significant challenge for novel drug development. The aim of this review is to present peptides of human and animal origin with antinociceptive potential and to show the possibilities of their modification, as well as the design of novel structures. The study presents the current knowledge on structure-activity relationship in the design of peptide-based biomimetic compounds, the modification strategies directed at increasing the antinociceptive activity, and improvement of metabolic stability and pharmacodynamic profile. The procedures employed in prolonged drug delivery of emerging compounds are also discussed. The work summarizes the conditions leading to the development of potential morphine replacements