1: Curr Top Med Chem. 2005;5(3):357-67.


The function of the extracellular regions in opioid receptor binding: insights from computational biology.

Paterlini MG.

Certusoft, Inc. 7900 West 78th Street, Suite 165, Minneapolis, MN 55439, USA. germana@certusoft.com

Pain management using opioid analgesics strives to achieve three goals: maximum efficacy, minimal risk of tolerance and physical dependence, and negligible side effects. Following the cloning of opioid and nociceptin receptors, novel ligands can be designed to target specific residues of these membrane proteins with the goal of improving efficacy and reducing side effects through selectivity. For the most part, ligand design has focused on binding sites located in the transmembrane region of the receptors, and has ignored the extracellular domains. In this review, we discuss the evidence for the interaction of the extracellular regions with opioids and show how computational biology tools can be used to model these domains for use in drug discovery. A computational model of the kappa-opioid receptor which includes the loop regions is presented. The model combines knowledge-based information, bioinformatics and computational tools to identify regions of the extracellular loop domains that can be targeted by drug design.

Publication Types:
Review

PMID: 15857317 [PubMed - indexed for MEDLINE]

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2: Mol Pharmacol. 2001 Jul;60(1):20-5.


Regulation of opioid receptor function by chronic agonist exposure: constitutive activity and desensitization.

Chavkin C, McLaughlin JP, Celver JP.

Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA. cchavkin@u.washington.edu.

Publication Types:
Review

PMID: 11408596 [PubMed - indexed for MEDLINE]

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3: Masui. 1996 Sep;45(9):1060-66.


[Molecular biological study on structure and function of the opioid receptor]

[Article in Japanese]

Fukuda K.

Department of Anesthesia, Kyoto University Hospital.

Pharmacological actions of opioid analgesics are mediated by the mu-, delta- and kappa-opioid receptors in the nervous system. To understand the molecular basis of the opioid receptor functions, experiments using molecular biological methods have been performed. Amino acid sequences elucidated by cDNA cloning revealed that the opioid receptor possesses characteristic structural features of the G-protein-coupled receptor family, including the presence of seven transmembrane segments. Furthermore, molecular mechanism for the ligand selectivity of the mu- and delta-opioid receptors was investigated by analyzing chimeric receptors between the mu- and delta-receptors and mutant receptors with one amino acid replacement.

Publication Types:
English Abstract
Review

PMID: 8905940 [PubMed - indexed for MEDLINE]

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4: Endocr Rev. 1988 May;9(2):200-12.


The molecular basis of opioid receptor function.

Simonds WF.

Molecular Pathophysiology Section, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.

An extensive body of pharmacological data demonstrates the existence of at least three opioid receptor subtypes mediating the diverse effects of opioids. Distinct binding and activity profiles of highly selective ligands, variable sensitivity to naloxone antagonisms, and selective protection and inactivation experiments strongly suggest that mu-, delta-, and kappa-opioid receptors represent recent discrete molecular entities. Purification and affinity labeling of receptor subunits are beginning to provide confirmation of this concept. The delta-opioid receptor affinity labeled and purified to homogeneity from NG108-15 cells comprises a glycoprotein subunit of Mr58,000 with one mol ligand bound/mol protein. Antibodies to this protein recognize native receptor in detergent solution and selectively bind to the Mr58,000 protein on immunoblots of partially purified preparations. Purification of the mu-opioid receptor from bovine striatum reveals a glycoprotein of Mr 65,000 which demonstrates opioid binding activity. Purification and affinity-labeling studies from other laboratories suggest a smaller size of Mr 58,000 for the mu-receptor however. The kappa-opioid receptor from guinea pig brain exhibits a unique mobility on sucrose density gradient centrifugation but has not been characterized in purified form. The primary structure of the opioid receptors, although unknown at present, will most likely reflect structural features of other inhibitory receptors coupled to G-proteins, with seven transmembrane helices and a large third cytoplasmic loop. Biochemical evidence clearly demonstrates the coupling of opioid receptors to Gi, accounting for opioid inhibition of adenylyl cyclase in neuronal cell culture and brain. Opioid inhibition of adenylyl cyclase has been reconstituted in IAP-treated NG108-15 cell membranes with a Gi preparation from brain. Electrophysiological evidence suggests that mu- and delta-opioid receptors can couple to a G-protein which mediates activation of inwardly rectifying potassium channels, perhaps to the same Gk mediating muscarinic potassium channel activation in heart. kappa-Opioid receptors are coupled to inhibition of voltage-dependent calcium channels in several neuronal systems. In NG108-15 cells opioid inhibition of calcium conductance is IAP sensitive and can be reconstituted with G-proteins purified from brain. Differences in the primary structure of mu-, delta-, and kappa-opioid receptors, as well as possible novel opioid receptor subtypes, will be defined by molecular cloning of recombinant DNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication Types:
Review

PMID: 2841104 [PubMed - indexed for MEDLINE]