Delta receptors opioids

Thomas, J.B., Herault, X.M., Rothman, R.B., Atkinson, R.N., Burgess, J.P., Mascarella, S.W., Dersch, C.M., Xu, H., Flippen-Anderson, J.L., George, C.F., Carroll, F.I. Factors influencing agonist potency and selectivity for the opioid delta receptor are revealed in structure-activity relationship studies of the 4-[(N-substituted-4-piperidinyl)arylamino]-N,N-diethylbenzamides, J. Med. Chem. 2001, 44, 972-987. 

Cotton R, Giles MG, Miller L, Shaw JS, Tims D. ICI174,864 a highly selective anatgonist for the opioid delta-receptor. Eur J Pharmacol 1984 97 331-332. 

Delorme D, Berthelette C, Lavoie R, Roberts E (1998) Asymmetric synthesis of diarylmethy-lamines preparation of selective opioid delta receptor ligands. Tetrahedron Asymmetry 9 3963-3966... 

Thomas JB, Herault XM, Rothman RB et al (2001) Factors influencing agonist potency and selectivity for the opioid delta receptor are revealed in structure-activity relationship studies of the 4-[(N-substituted-4-piperidinyl)arylamino]-N,N-diethylbenzamides. J Med Chem 44 972-987... 

The relative extent of the unwanted effects caused by selective agonists at the different opioid receptors is of great importance in determining if non-mu opioids will have better spectra of actions as compared to morphine. However, there are good indications that the kappa and delta receptor agonists cause less respiratory depression than mu... 

Delta receptors are relatively selective for two related penta-peptides, methionine enkephalin and leucine enkephalin (met- and leu-enkephalin), which were isolated from porcine brain (Hughes 1975). Both met- and leu-enkephalin inhibit electrically induced contractions of guinea pig ileum, an effect that mimics those effects seen with opioid drugs, and is naloxone reversible. The enkephalins are processed posttranslational ly from proenkephalin, and secreted from central and peripheral neurons and endocrine cells in the adrenal medulla. 

The third prohormone from which opioid peptides are derived is pro-opiomelanocortin, which yields a number of nonopioid and opioid peptide products (O Donohue and Dorsa 1982). Of these products, beta-endorphin, an untriakontapeptide isolated from camel pituitary gland by Li and Chung (1976)) is thought to interact primarily with mu and delta receptors. 

The biochemical and pharmacological properties of the kappa receptor and the differences between the kappa, mu and delta receptors have been reviewed elsewhere. The reader is directed to the opioid review articles by Rees and Hunter (1990) [4], Casy (1989) [3] and Leslie (1987) [10] and also to two shorter reviews which deal specifically with kappa agonists the review by Horwell published in 1988 entitled Kappa Opioid Analgesics [8] and the review by Millan in 1990 on kappa opioid receptors and analgesia [9]. An account of the medicinal chemistry of selective opioid agonists and antagonists was published in 1990 by Zimmerman and Leander [5]. 

Vaught, J.L., Rothman, R.B., Westfall, T.C. Mu and delta receptors their role in analgesia in the differential effects of opioid peptides on analgesia, Life Sci. 1982, 30, 1443-1455. 

Jiang, Q., Takemori, A.E., Sultana, M., etal. Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5 -isothiocyanate evidence for delta receptor subtypes, J. Pharmacol. Exp.Ther. 1991, 257, 1069-1095. 

Sold as Dilaudid in the U.S., hydromorphone is a semisynthetic, differing from morphine only by presence of a 6-keto group, and the hydrogenation of the double bond at the 7-8 position of the molecule.57 Like morphine, it acts primarily at the mu opioid receptors, and to a lesser degree at delta receptors. 

The existence of several classes of opioid receptors has therefore lead to the development of drugs that are somewhat more selective in the receptor class or subclass that they stimulate. In particular, drugs that selectively stimulate kappa or delta receptors may still provide sufficient analgesia, but will be less likely to provoke problems like respiratory depression and opioid abuse if they avoid or even block (antagonize) the mu receptors. Certain opioid drugs, for example, stimulate kappa receptors while avoiding or blocking... 

All opioids produce their effect by activating one or more of the three types of receptors. Thus analgesia involves the activation of the mu receptors that are located mainly at supraspinal sites and kappa receptors in the spinal cord delta receptors may also be involved but their relative contribution is unclear. Nevertheless, the actions of the opioids on these receptors is complex, as there is evidence that the same substance may act as a full agonist, or as an antagonist at different sites within the brain. 

The endogenous opioid peptides have a range of affinities for the different types of opioid receptor. Some met-enkephalin derivatives, for example, show affinity for mu and delta receptors, whereas other peptides, derived from proenkephalin, show a preference for the delta sites. All peptides from prodynorphin act predominantly on kappa sites, while beta-endorphin behaves like the enkephalins and shows selectivity for the mu and delta sites. 

Today, we know that there are three types of opioid receptors—mu, delta, and kappa receptors [see review 3]. Proenkephalin contains six copies of Met-enkephalins and one copy of Leu-enkephalin. Enkephalins, especially Leu-enkephalin, are believed to be selective to delta receptors. Opiomelano-cortin contains (3-endorphin that has the Met-enkephalin at its amino terminus. (3-Endorphin is a nonselective ligand for mu and delta receptors. 

Prodynorphin contains three copies of Leu-enkephalin with carboxy-termi-nus extended polypeptides of various lengths known as dynorphin A (or dynorphin 1-17), dynorphin B (dynorphin 1-13), or a- and 3-neoendorphin. These peptides derived from prodynorphin are selective to kappa receptors and can also be further broken down to Leu-enkephalin. The identification of the delta receptor (or the enkephalin receptor) was a direct consequence of the discovery of enkephalins. This chapter will review the major events that are important for the identification of delta receptors and the subsequent cloning of delta receptor genes, and eventually all other opioid receptor genes. 

Although above mentioned delta and mu receptor selective peptides and opiates were observed and useful for the identification of distinctive delta receptor from other opioid receptors, they suffered from the low selectivity and cross-actions at high doses or concentrations of these ligands, especially in in vivo pharmacological studies. The needs of having highly selective ligands for all types of opioid receptors were clear. In addition to the above... 

---