Opioid receptor subtypes

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

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

Figure 5.1 Visualization of the distribution of the DA transporter, D3 receptor, and K2-opioid receptor in the human brain of a drug-free control subject and a representative cocaine overdose victim. (A, B) The DA transporter was measured using [3H]WIN 35,428 (2 nM) as described previously. (C, D) The D3 receptor was measured using [3H]-(+)-7-OH-DPAT (1 nM) in the presence of GTP (300 m/W) to enhance the selective labeling of the D3 receptor subtype over the D2 receptor subtype as described previously. (E, F) The K2-opioid receptor subtype was measured using [125l]IOXY on tissue sections pretreated with BIT and FIT to occlude binding to the p- and 8-opioid receptors, respectively.

Sofuoglu M, Portoghese P, Takemori A. Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice evidence for delta opioid receptor subtypes. 

Perez, L. and Lysle, D.T., Conditioned immunomodulation Investigations of the role of endogenous activity at mu, kappa, and delta opioid receptor subtypes, J. Neuroimmunol.,19, 101,1997. 

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). 

Bodnar RJ. (1996). Opioid receptor subtype antagonists and ingestion. In Drug Receptor Subtypes and Ingestive Behavior, Cooper SG, Ciifton PG, eds. London Academic Press, pp. 127-46. 

Mignat C, Wille U, Ziegler A. (1995). Affinity profiles of morphine, codeine, dihydrocodeine, and their glucuronides at opioid receptor subtypes. Life Sci. 56(10) 793-99. 

The chemical structures and biological activities of hundreds of opioid analgesics derived from the prototype opioid drug morphine are most comprehensively described in two books published in 1986, one entitled Opioid Analgesics, Chemistry and Receptors by Casy and Parfitt [1] and the other entitled Opiates by Lenz et al. [2]. Follow-up articles include those by Casy in 1989, entitled Opioid Receptors and their Ligands Recent Developments [3] which also includes sections on opioid peptides, affinity labelling and opioid receptor subtypes Rees and Hunter in 1990 [4] covering the... 

The biological methods used for in vitro and in vivo study of opioid receptors are described by Leslie [10] in a review which includes useful tables summarizing the opioid receptor subtypes present in various biological tissues, and the binding selectivity of several standard reference opioid ligands. 

The majority of studies aimed at preparing kappa-selective opioids have used U-50488 (5) as the chemical lead and, as the above discussion shows, this has proved to be a highly productive approach. However, as was pointed out above, there are other structures [EKC (3), tifluadom (6) and the peptide dynorphin (7)] which have been reported to bind to the kappa receptor, albeit with poor opioid receptor subtype selectivity. Some attempts have been made to develop kappa-selective ligands from these structures and they are summarized here. 

Table 1. Main responses of the two best-characterized opioid receptor subtypes...

Table 31-1 Opioid Receptor Subtypes, Their Functions, and Their Endogenous Peptide Affinities. ...

Bolan EA, Tallarida RJ, Pasternak GW Synergy between mu opioid ligands Evidence for functional interactions among mu opioid receptor subtypes. J Pharmacol Exp Ther 2002 303 557. [PMID 12388636]... 

Opioid receptor subtypes This was later confirmed by binding experiments with... 

While opioid peptides have been very useful for investigating the pharmacology of different opioid receptor subtypes, pharmacological investigations have established that no pharmacodynamic advantage is to be expected from opioid peptides with respect to analgesic activity or side-effects. Furthermore, they have their own shortcomings with respect to potential clinical applications. Most importantly their peptidic structure usually prohibits administration by the oral or transdermal route, which are the routes of choice for pain treatment. 

Hohlweg, R., Watson, B.T., Petterson, I. (Novo Nordisk) Novel triazaspirodecanones with high affinity for opioid receptor subtypes, WO0136418 (2001). 

The precise functions of the opioid receptor subtypes remain to be delineated. In many studies, it has been established that they modulate the functions of the dopaminergic system. For example, administration of morphine into the area 10 region results in a dopamine-dependent increase in locomotor activity. Electiophysiological studies of area 9 neurons suggest that p and k opioids have opposite effects on motor behaviors activation or sedation, respectively. The k and p agonists have also been found to exert opposite actions with respect to fluid regulation diuretic and... 

Table 31-1. Opioid Receptor Subtypes, Endogenous Opioid Peptide Affinity, and Some of Their Functions. ...

Using superfusion experiments, electrophysiological techniques, pithed animal preparations, and experiments in which transmitter release was determined indirectly via the end-organ response (e.g., twitch response of vas deferens preparations), numerous presynaptic opioid receptors have been identified (Table 2). For the identification of the receptors, classical drug tools were used for future studies, knockout mice (now available for each of the four opioid receptor subtypes) and special nucleotides (e.g., antisense oligodeoxynucleotides or short interfering... 

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