Opioid receptors dimerization

Bhushan RG, Sharma SK, Portoghese PS. Design and synthesis of kappa-delta opioid bivalent ligands as probes to study opioid receptor dimerization. 224th ACS National Meeting, Boston, 2002 MEDI-242. 

Portoghese, P. S. From models to molecules opioid receptor dimers, bivalent ligands, and selective opioid receptor probes. J. Med. Chem. 2001, 44, 2259-2269. 

FIGURE 9.19 Dimeric antagonist formed by oligoglycyl-based linkage of two opioid receptor subtype antagonists naltrindole and ICI-199,441. From [59],... 

Application of the SCM method to the opioid receptor subtypes (187,188) supported the experimental evidence of subtype specificity in the process of heterodimerization of these receptors (96). Although likely heterodimerization interfaces of the 5-p and 5-k opioid receptor complexes were predicted using the SCM method, the application of this procedure to explore the putative interface between p and k opioid receptors resulted in a null set for residues that indicates the absence of a predicted dimerization interface. This result is in full agreement with previous experimental observations (96). 

Cvejic, S. and Devi, L. A. (1997) Dimerization of the delta opioid receptor implication for a role in receptor internalization. J. Biol. Chem. 272,26959-26964. 

Filizola, M. and Weinstein, H. (2002) Structural models for dimerization of G protein coupled receptors the opioid receptor homodimers. Biopolymers (Peptide Sci.) 66, 317-325. 

Agonist occupancy of GPCRs, such as the delta opioid receptor, leads to physiological effects through interactions with heterotrimeric G proteins. Such G proteins consist of a Ga subunit and its Gpy dimeric partner. There are four major families of Ga proteins with different profiles of effector interaction 1) Gas, which activate adenylyl cyclase 2) Gai/o, so-called inhibitory G proteins named for their ability to inhibit adenylyl cyclase, but interact with many effectors 3) Gaq/11, which activate phospholipase C- 3 (PLC- 3) and 4) Gal2/13, which may regulate small GTP-binding proteins. Delta opioid receptors, like mu and kappa opioid receptors, couple to mem-... 

Within the four families of Ga proteins 20 different subunits have been identified. In addition, five different (3 subunits and 12 y subunits have been described. Although not all of these are able to form (3y dimers, there is obviously a potential for numerous combinations of Ga, G(3, and Gy subunits that could interact with the delta opioid receptor. The particular combinations in a cell could be important in governing which signaling pathways are activated. 

The classical opioid receptors, mu, delta, and kappa, have led to an even further definition of the relative pharmacology previously associated with them [12]. Moreover, it has more recently been reported that opioid receptors can exist as heterodimers [13]. This remarkable discovery opens the future of ligand design to target these dimeric and potentially oligomeric forms of the opioid receptor complexes. 

Receptor Subtypes, Splice Variants, and Receptor Dimerization, Before cloning of the opioid receptors, subtypes of each of the three opioid receptors were proposed on the basis of evidence from pharmacological assays (see Refs. 69, 103 for excellent reviews), although opioid receptors identified by cloning have consistently represented only a single subtype for each receptor type. Currently, there is still considerable debate on the existence and nature of some of these receptor subtypes. 

Recently, an alternative explanation for opioid receptor subtypes, receptor dimerization, has appeared in the literature that could explain why different gene products have not been identified for the proposed receptor sub-types in spite of the evidence from pharmacological assays for their existence. The details of these studies are discussed under Recent Developments (Section 7.1) below. 

Table 7.16 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of Dimeric Enkephalin Analogs...

The eighth chapter, Twin and Triplet Drugs in Opioid Research, by Hideaki Fujii, presents opioid research that used dimer and trimer ligands as a tool for investigating opioid receptors. The dimer and trimer constructs were able to increase ligand activity and selectivity. 

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