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Opiate analogs selective for the delta-opioid receptor

a technology of opiate analogs and delta-opioid receptors, applied in the field of pharmacology, can solve the problems of complex use of morphine, poor selectivity, low efficacy in vivo, etc., and achieve the effect of decreasing gastric secretion

Inactive Publication Date: 2007-05-10
WELSH WILLIAM J +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The novel compounds demonstrate superior oral tolerability, increased bioavailability, and reduced side effects, making them promising for pain management and immune disorder treatments with enhanced safety profiles.

Problems solved by technology

However, use of morphine is complicated by the highly addictive nature of this narcotic.
Several examples of non-peptide ligands have been discovered either by modification of morphine-type alkaloids or by random screening approaches (Portoghese et al., 1993; Knapp et al., 1995; Knapp et al., 1996), but most of these suffer from various problems such as poor selectivity and low efficacy in vivo.

Method used

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  • Opiate analogs selective for the delta-opioid receptor
  • Opiate analogs selective for the delta-opioid receptor
  • Opiate analogs selective for the delta-opioid receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

Three Dimensional Structure-Activity Relationship (3D-QSAR) Models

[0113] The inventors employed approaches in computer-aided molecular design (CAMD) to develop 3-dimensional quantitative structure-activity relationship (3D-QSAR) molecular models based on a series of known opioids for which experimental binding data are available (Raynor et al., 1994). These 3D-QSAR models were used as tools to guide the design of novel, more potent, molecules and to predict their biological activity prior to the time-consuming chemical synthesis and biological testing of all possible candidates. By using 3D-QSAR models to filter or screen out the less active candidates, resources can be focused on the most promising candidates thereby accelerating the drug discovery process.

[0114] Initial structural geometries were obtained from the published x-ray crystal structures of several opioids included in this study. Each molecular structure was geometrically optimized within the Sybyl molecular modeling ...

example 2

Design of Novel δ-selective Opioids: Analogues of NTI and SIOM

[0118] Using the 3D-QSAR models and pharmacophoric maps, a large number of novel NTI and SIOM analogs (>100) that retain or exceed the δ-receptor affinity and selectivity of NTI and SIOM yet exhibit improved bioavailability, were computer-designed. The binding affinities (pK1) of these novel molecules, for all three opioid receptors (δ, κ, and μ), were predicted using the appropriate 3D-QSAR model. The results for a subset of these novel molecules are summarized in FIG. 4 for the NTI analogues and in FIG. 5 for the SIOM analogues. Many of these novel compounds are predicted to exhibit equal or superior binding affinity and selectivity for the δ receptor compared with NTI (far left in FIG. 4) and SIOM (far left in FIG. 5). It should be noted that both NTI (a δ antagonist) and SIOM (a δ agonist) possess high binding affinity and high selectivity for the 8 opioid receptor.

[0119] The δ-receptor binding affinity and selectiv...

example 3

Chemical Synthesis

[0124] The synthesis of SIOM-based analog, OP-26 is given in Scheme 4. The synthesis indole-based analogs (OP-44 derivatives) is provided in Scheme 5.

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Abstract

Novel compounds which selectively bind to the δ-opioid receptor have been designed. These compounds have greater selectivity, improved water (blood) solubility, and enhanced therapeutic value as analgesics. Because agonists with selectivity for the δ-opioid receptor have shown promise in providing enhanced analgesis without the addictive properties, the compounds of the present invention are better than morphine, naltrindole (NTI), spiroindanyloxymorphone (SIOM), and other known μ-opioid receptor selectors as analgesics.

Description

[0001] The present application claims priority to co-pending U.S. Provisional Application, Ser. No. 60 / 411,724 filed Sep. 18, 2002. The entire text of the above-referenced disclosure is specifically incorporated herein by reference without disclaimer.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates generally to the fields of pharmacology and more specifically to compounds and treatments for pain management, immune disorders, and drug addiction. More particularly, it provides a variety of compositions and methods based on novel opiate analogs having improved δ opioid receptor selectivity. [0004] 2. Description of Related Art [0005] Opioid analgesics are well known for their ability to reduce the perception of pain without a loss of consciousness. Opium, the source of natural opiates, contains a variety of opiates including the familiar morphine and codeine. Morphine possesses a variety of effects, among which are increased tolerance to...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/485C07D489/02A61P25/04C07D471/10C07D471/22C07D489/08C07D491/20C07D491/22C07D498/08
CPCC07D471/10C07D498/08A61P1/00A61P1/14A61P9/00A61P11/00A61P25/00A61P25/04A61P25/32A61P25/36A61P29/00A61P37/00A61P37/06A61P37/08
Inventor WELSH, WILLIAM J.YU, SEONG JAENAIR, ANIL
Owner WELSH WILLIAM J
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