Targeting truncated G‐protein coupled opioid receptors for treatment of pain without side‐effects

Classical pharmacological approaches have implied the existence of subtypes of opioid receptors. This concept was confirmed with the cloning of three opioid receptor genes for mu, delta and kappa 1 drugs. We examined the mu opioid receptor (MOR‐1) gene (Oprm1) in greater detail and identified a vast array of splice variants. There are two primary classes generated by different promoters. The primary promoter is associated with exon 1 and generates a large number of traditional 7 transmembrane domain receptors. The second promoter, associated with exon 11 generates a number of truncated, 6 transmembrane domains. Using a novel radioligand, 125 I‐BNtxA synthesized in our laboratories we have now identified a novel exon11‐associated binding site remaining in the exon 1 KO mice, but lost in the exon 11 KO mice. IBNtxA is an effective analgesic. This analgesia persists in the exon 1 KO mice, but is lost in the exon 11 KO mice. The selectivity of this site is quite unique, with morphinans and benzomorphans showing very high affinity while drugs like morphine and the antagonist naloxone bind very poorly. This selectivity is supported by antagonist studies in vivo. IBNtxA shows the absence of constipation, respiratory depression, physical dependence, reward. It shows no cross tolerance to morphine and can be given to morphine‐dependent mice without a decrease in its analgesic actions or the precipitation of withdrawal. Thus, this ligand comes close to the ideal opioid analgesic through a novel receptor target comprising truncated 6 transmembrane domain splice variants of the mu opioid receptor MOR‐1. IBNtxA is an ideal opioid analgesic and can be used as a lead compound to design a library of opioid analgesics.