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DEVELOPING A SCREENING PLATFORM THAT TARGETS OPIOID RECEPTOR HETERODIMERS
Collaboration with Whistler Lab

G protein coupled receptors (GPCR) are major drug targets and represent around 50% of all prescription drugs currently marketed, thus it is not surprising that the market for GPCR based drugs is one of the largest.   Within this family, opioid receptors, which are activated by drugs such as morphine, inhibit pain.  Some 87 million Americans and over 290 million individuals worldwide suffer from some form of chronic pain.   For centuries opioids have been used for the treatment of pain.  A major limitation to the long term use of opioids is the development of physiological tolerance (a profound decrease in analgesic effect observed in all patients during prolonged administration), physiological dependence in some patients (a requirement for continued administration of increasing doses of drug to prevent the development of symptoms of opiate withdrawal), and debilitating side-effects (such as nausea, vomiting, and constipation).  The development of new opioid drugs for the treatment of chronic pain is also limited due to drug abuse liability.  For example, the number of Americans reporting abuse of prescription medications was higher than the combined total of abuse of cocaine, hallucinogens, inhalants and heroine (NIDA, 2001; SAMHSA, 2005; NSDUH, 2005).  Recent evidence from many laboratories have shown that GPCR form both oligomers and heterodimers with other receptor complexes (for reviews see: Devi, 2001; Milligan, 2004; Prinster et al., 2005; Terrillon and Bouvier, 2004).  This has been shown to be the case for the opioid receptors (Cvejic and Devi, 1997; Jordan and Devi, 1999; Devi, 2001) and recently shown to have in vivo functional consequences for the treatment of pain (Waldhoer et al., 2005).

Why the Development of an Opioid Receptor Heterodimerization Platform is Necessary

Heterodimer-specific binding sites change the way we view ‘traditional pharmacology’ and offer new tools for drug discovery that will lead to generation of new compounds which specifically target opioid receptor heterodimers and not monomers. These receptor complexes produce unique ligand binding sites that have different pharmacological profiles compared to the individual receptors alone.  The unique landing pads generated by a receptor (Figure 1), when it is complexed in heterodimers with other opioid receptors, has not been fully exploited as targets for the treatment of pain.  The Whistler Lab at the Gallo Center was the first to show that the DOP-KOP heterodimer receptor specific compound 6’-GNTI caused analgesia when delivered into the spinal cord but not when it was delivered into the brain, thus reducing the degree of side effects (Waldhoer et al., 2005).    Multispan Inc. is a company specializing in the commercialization of GPCR reagents and has already established itself as a leader in the production and characterization of cell lines expressing single receptors.  Multispan Inc will use the cell lines we produce to develop a high throughput screening platform.  The longer-term aim of this project is to develop heterodimer-specific drugs that have greater tissue specificity, limited tolerance and dependence and improved side effect profile with reduced drug abuse liability.


Opioid_Dimer.jpg
Figure 1. The functional response to the binding of 6'-GNTI is different for the three forms of the opioid receptor presented: DOP-R (A), KOP-R (C), and delta-kappa (DOP-KOP-R) heteromer (B). Only the heteromeric complex (B) is capable of producing a robust response to the analgesic (Park and Palczewski, 2005).

Purpose of Project

The Small Business Technology Transfer Program (STTR) provides an opportunity to accelerate the transfer of technology identified at the Gallo Center to Multispan Inc.  Multispan Inc’s focus will be on the commercialization of the opioid receptor heterodimerization research tools and technologies into a drug discovery platform that will lead to new compounds for the treatment of pain, and facilitate the development of reagents to further delineate the role of opioid receptor dimers in the development of opiate tolerance, dependence and as a mechanism to limit drug abuse liability potential.