P-Opioid receptors affinity

Findings continue to accumulate in the field of endogenous opiates, as exemplified by two tetrapeptides isolated from mammalian brain and found to have high affinity and selectivity for p-opioid receptors. These tetrapeptides are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2). A number of synthetic analogues have been prepared with the view to improve their metabolic stability and, in some cases, to limit their access to peripheral opioid receptors. The three synthetic endomor-phin analogues Tyr-D-Ala-Phe-Phe-NH2 (6.84), Tyr-D-Arg-Phe-Phe-NH2 (6.85), and Tyr-D-Arg-Phe-Ape-NH2 (6.86), to be discussed in the next section, have potent antinociceptive effects in in vivo inflammatory tests but exhibit modest effects in the CNS. However, and despite the presence of a D-amino acid and a protected C-terminus, they remained sensitive to enzymatic hydrolysis [211][212],... 

Opioid receptor binding Diamorphine (Inturrisi et al., 1983) has a 10-100fold lower p-opioid receptor binding affinity than morphine. The relevant opioid properties originate from the high p-receptor affinity of the metabolites 6-acetylmorphine and morphine (Umans and Inturrisi, 1981). 

Opioid receptor binding Etorphine (Lee et al., 1999) has a high affinity and selectivity for the p-opioid receptor. 

Opioid receptor affinity Ketobemidone is a p-selective synthetic opioid with a receptor affinity similar to morphine (Christensen, 1993). 

Opioid receptor binding Levomethadone is the more potent and p-selective levo-enantiomer of racemic methadone (Sim, 1973). It has an opioid receptor affinity in the range of morphine. 

Opioid receptor affinity Tramadol (Frink et al., 1996) itself has a weak opioid receptor affinity, the active metabolite O-desmethyl-tramadol has p-selectivity and p-affinity about 10 times lower than that of morphine. 

However, the above-mentioned benzomorphans and morphinans are not the only compounds reported to have affinity for both the NMDA receptor and the p-opioid receptor. There have been several reports on the NMDA... 

These discoveries were followed by the isolation of cDNA for two opioid receptors derived from rat brain, identified as ROR-A and ROR-B [55], Competition studies performed with DSLET, DPDPE, and DAMGO in transfected CHO cells determined that the ROR-A corresponds to the 6-opioid receptor and ROR-B corresponds to the p-opioid receptor [55]. Finally, human cDNA for the 6-opioid was expressed in COS-7 cells [56]. Again, competition studies confirmed the presence of the 6-opioid receptor. Moreover, it was determined that the cloned receptor represents the 62-opioid receptor, since NTB showed an approximately eightfold greater affinity than BNTX [56]. The molecular biology of the cloned opioid receptors has since been reviewed [57]. It has been subsequently determined that the cloned 6-opioid receptor may correspond to the 62-isoform [57]. 

Opioid receptor affinity labels have been reported for other narcotic analgesics, for example, piperidines, 293 294 benzomorphans, 295 296 and mor-phinans, 297,298 and the topic is further discussed in Chapter 13 (p. 445). Not only is the oxo-function in the 4,5-epoxymorphinan C-ring available for ready elaboration, but C-6 substituents, although they affect agonist potency, do not impair unduly receptor affinity. 299 301 ... 

Sufentanil, a fentanyl analogue, is a highly lipid-soluble synthetic opioid with high affinity for OP3 (p) opioid receptors and a potency some 5-10 times that of fentanyl. It is a short-acting analgesic. 

Mu-Receptor Antagonists Derived from Somatostatin. Potent p-opioid antagonists have been identified that are derivatives of somatostatin rather than of an opioid peptide (see Ref 656 for a review). Somatostatin exhibits low affinity for opioid receptors, and the potent somatostatin analog SMS-201,995 (D-Phe-cycZo[CyS Phe-D-Trp-Lys-Thr-Cys]-Thr-ol) was found to be an antagonist at p, opioid receptors (940). Further structural modification yielded a series of peptides with the general structure D-Phe-cycZo[Cys-Tyr-D-Trp-X-Thr-Pen]-ThrNH, where X = Lys, Om, or Arg in CTP, CTOP (19, Fig. 7.4), and... 

Peptides and Peptidomimetics from Combinatorial Libraries. Mixture-based combinatorial peptide libraries have been extensively explored by Houghten and coworkers and have led to the identification of a variety of peptides with affinity for opioid receptors (see Ref 946 for a review). Early hexapeptide libraries, deconvoluted by binding to p opioid receptors and either iterative deconvolution (947)or positional scanning (948 see Ref 946 for a description of these deconvolution techniques), identified sequences related to the enkephalins. Other nonacetylated peptide libraries have identified more varied peptides, some that resemble opioid peptides and some that do not. Iterative deconvolution of a hexapeptide library resulted in identification of both Tyr-Pro-Phe-Gly-Phe-XNH, (X = one of 20 natural amino acids), reminiscent of the... 

Among the most indispensable analgesics, morphinan-6-ones such as oxymor-phone, oxycodone, and dihydromorphinone have their main importance in clinical use. As earlier shown, hydrazone, oxime, carbazone, and semicarbazone derivatives of these morphinan-6-ones exhibit high affinity at the p-opioid receptor [54-56] and exhibit high antinociceptive potency in addition to less pronounced side effects [19, 57-60]. Therefore, it remains a promising synthetic task to convert the carbonyl group into various functionalities. 

Spetea M, Toth F, Schiitz J, Otvos F, Toth G, Benyhe S, Borsodi A, Schmidhammer H (2003) Binding characteristics of [3H] 14-methoxymetopon, a high affinity p-opioid receptor agonist. Eur J Neurosci 18 290-295... 

In the (+)-2 series, the me la diethyl amide derivative retained high affinity for 8 as well as for p opioid receptors. Movement of the diethyl amide from the para to the meta position resulted in less 8 selective ligands with a mixed 8/p agonist profile in these series. Changing the meta-diethylamide to a meta-V-methylanilide resulted in potent mixed 8 and p agonists [39]. 

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