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Pharmacological Characterization of Human κ / μ Opioid Receptor Chimeras that Retain High Affinity for Dynorphin A

[ Vol. 5 , Issue. 3 ]


Robert N. DeHaven, Erik Mansson, Jeffrey D. Daubert and Joel A. Cassel   Pages 303 - 313 ( 11 )


Arylacetamide analgesics that stimulate k opioid receptors in the central nervous system mediate dysphoria and psychosis as well as analgesia. However, the naturally occurring peptide agonist, dynorphin A, is analgesic in the absence of dysphoria and psychosis, indicating that the therapeutic effects of k opioid agonists may be separated from their side effects. As part of our effort to discover κ opioid receptor analgesics lacking side effects, we designed and constructed two μ/κ chimeric receptors, composed primarily of amino acid residues derived from the μ opioid receptor, that were expected to bind dynorphin A with high affinity. In one, extracellular loop 2 and transmembrane domain 4 were derived from the κ opioid receptor and in the other, only extracellular loop 2 was derived from the κ opioid receptor. Most competitors of [3H]diprenorphine binding from a variety of structural classes bound to the chimeras with affinities similar to those with which they bound to the m opioid receptor. In contrast, dynorphin A analogs bound to the chimeras with affinities similar to those with which they bound to the κ opioid receptor. Pharmacological characterization of [35S]GTPgS binding mediated by the chimera with extracellular loop 2 derived from the κ opioid receptor showed that it behaved as if it were m opioid receptor with high affinity for dynorphin A analogs. These chimeras may be useful in identifying novel κ receptor agonists that bind to the second extracellular loop of the receptor and share the desirable therapeutic profile of dynorphin A.


analgesics, opioid receptor, opioid agonist, arylacetamides, benzomorphan, transmembrane domain, chinese hamster ovary (cho)


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