Delta receptors subtypes

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. 

Rady, J.J., A.E. Takemori, P.S. Portoghese, and J.M. Fujimoto, Supraspinal delta receptor subtype activity of heroin and 6-monoacetyhnorphine in Swiss Webster mice, Life Sci., 55(8), 603-609, 1994. 

Morphine is a naturally occmring alkaloid from the opium poppy seed. Modern formulations employ synthetic morphine. Major and minor sites of morphine activity include spinal and supraspinal opioid receptors. Morphine binds to and activates mu, kappa and delta receptor subtypes. 

If opiates are such addictive and potentially lethal compounds, why does the body respond to them As with the cannabinoids (Chapter 7), it has been discovered that the body and brain possess numerous opiate-specific receptor sites. As many as nine receptor subtypes have been identified, with three of them being the most important p (mu), k (kappa) and 8 (delta). The finding that the distribution of opiate receptors did not parallel the distribution of any known neurotransmitter prompted the search for and identification of a number of endogenous compounds specific to these receptors. These enkephalins and endorphins are manufactured within the brain and other body systems (especially the gut and intestines) and form the body s natural response to pain. They appear to be produced in bulk chains of amino acids called polypeptides , with each active neurotransmitter being composed of around five amino acid molecules. These active neurotransmitters are subsequently cleaved from the larger polypeptides at times of demand for example, it has been demonstrated that the plasma levels of these active compounds rise during childbirth, traumatic incidents and vigorous physical exercise. 

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. 

Progress in the molecular characterization of opioid receptors has been slower than for other cell-surface receptors and, to date, none has been sequenced or cloned and the second messengers mediating opioid actions are still unknown. The literature in this area has been reviewed in 1990 by Lo and Smith [11], who cite three main problems with the opioid receptor it is difficult to solubilize, there are no simple biochemical assays to test the functional integrity of an isolated receptor extract and there are at least three receptor subtypes (designated as mu, kappa and delta). 

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

The different types and subtypes of opioid receptors in the nervous system. The mu (p), kappa (k) and delta (8) subtype are designated by corresponding Greek letters. 

Zaki PA, Bilsky EJ, Vanderah TW, Lai J, Evans CJ, Porreca F. Opioid receptor types and subtypes the delta receptor as a model. Annu Rev Pharmacol Toxicol 1996 36 379-401. 

Rothman and Westfall [3,4], divided the delta receptor population into two components one coupled to mu opioid receptors, and the other acting alone. The third hypothesis combined these ideas, by suggesting that the delta receptors that interact with the mu opioid receptors are different molecular entities from those that act alone [5,6]. A definitive test of the above hypotheses would be to identify two or more delta receptor proteins by molecular cloning. The cloning of the human delta opioid receptor [7] was the fortunate outcome of a larger project in our laboratory to clone of the cDNAs encoding putative delta opioid receptor subtypes. 

Since at the time of the described studies it was thought that the two delta receptor antagonists naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) were selective for the proposed delta-2 and delta-1 receptor subtypes, respectively [19], the relatively high affinity of NTB for the expressed receptors (as compared to BNTX, see Table 1) was thought to be consistent with the cloned human delta receptor being of the delta-2 opioid receptor subtype. 

Distinct genes for delta opioid receptor subtypes however, have not been identified, reducing the probability that delta opioid receptor subtypes exist as distinct molecular entities. On the other hand, this does not eliminate the possibility that pharmacological delta opioid receptor subtypes can be produced by alternative splicing from the cloned delta receptor genomic sequence, as was found for the other opioid receptors [28]. However, there is no evidence for alternative splicing for the delta opioid receptor of this at... 

D-Ala-DELTORPHINS RECOGNIZE TWO DELTA OPIATE RECEPTOR SUBTYPES... 

The Delta Opioid Receptor Subtypes and Pain Modulation... 

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