Portal de Periódicos da CAPES

The Third Extracellular Loop of the μ Opioid Receptor Is Important for Agonist Selectivity

1995; Elsevier BV; Volume: 270; Issue: 22 Linguagem: Inglês

10.1016/s0021-9258(18)92233-7

1083-351X

Ji-Chun Xue, Chongguang Chen, Jinmin Zhu, Satya P. Kunapuli, J. Kim de Riel, Lei Yu, Lee‐Yuan Liu‐Chen,

Pharmacological Receptor Mechanisms and Effects

To investigate the interaction between the opioid receptor and its ligands, we compared the binding of μ-selective ligands to two μ/κ chimeric opioid receptors and to μ and k receptors. The two chimeras were constructed from cloned rat μ, and k receptors in which a segment from the middle of the third intracellular loop to the C terminus was exchanged. When this portion of the k receptor was replaced by that of the μ receptor, affinities of μ selective agonists, DAMGO (Tyr-D-Ala-Gly-NMePhe-Gly-ol), PL017 (Tyr-Pro-NMePhe-D-Pro-NH2), sufentanil, and morphine, were greatly increased as compared to those for the k receptor. Conversely, when this region of the μ receptor was substituted by that of the k receptor, affinities for these agonists were substantially decreased as compared with those of the μ receptor. Unlike selective agonists, the μ-selective antagonist, CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-penicillamine-Thr-NH2), displayed a low affinity for both chimeric receptors, similar to that of the k receptor. Thus, the region from the middle of the third intracellular loop to the C terminus of the μ receptor is important for the binding of selective agonists. Conversely, the determinants for selective binding of the antagonist CTAP reside in a more extended region of the receptor. To investigate the interaction between the opioid receptor and its ligands, we compared the binding of μ-selective ligands to two μ/κ chimeric opioid receptors and to μ and k receptors. The two chimeras were constructed from cloned rat μ, and k receptors in which a segment from the middle of the third intracellular loop to the C terminus was exchanged. When this portion of the k receptor was replaced by that of the μ receptor, affinities of μ selective agonists, DAMGO (Tyr-D-Ala-Gly-NMePhe-Gly-ol), PL017 (Tyr-Pro-NMePhe-D-Pro-NH2), sufentanil, and morphine, were greatly increased as compared to those for the k receptor. Conversely, when this region of the μ receptor was substituted by that of the k receptor, affinities for these agonists were substantially decreased as compared with those of the μ receptor. Unlike selective agonists, the μ-selective antagonist, CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-penicillamine-Thr-NH2), displayed a low affinity for both chimeric receptors, similar to that of the k receptor. Thus, the region from the middle of the third intracellular loop to the C terminus of the μ receptor is important for the binding of selective agonists. Conversely, the determinants for selective binding of the antagonist CTAP reside in a more extended region of the receptor.