Receptor modeling opiate

Interaction of Model Opiate Anionic Receptor Sites with Characteristic JV-Substituents of Rigid Opiates PCILO and Empirical Potential Energy Calculations... 

In this study, as a first step in modeling opiate receptor interactions, we have considered the interaction of an ammonium ion and methyl sulfate or phosphate with the series of compounds shown in Figure 1. These compounds, as N-substitutents in rigid opiates such as 5,9 dimethyl, 2 hydroxy, 6,7 benzomorphans, exhibit a broad spectrum of pharmacological behavior from... 

Dobrenis K, Makman MH, Stefano GB (1995) Occurrence of the opiate alkaloid-selective p. receptor in mammahan microglia, astrocytes and Kupffer cells. Brain Res 686 239-248 Donahoe RM (2004) Multiple ways that drug abuse might influence AIDS progression clues from a monkey model. J Neuroimmunol 147 28-32... 

Several opiate receptors have been identified on cells of the nervous systems of animals and humans, with mu (p), kappa (k), and gamma (y) subtypes being predominant. These classical opiate receptors are G- protein coupled 7-transmembrane molecules.27 Opiates predominantly affect immune responses directly by ligation of p, k, and y opiate receptors, as well as non-classical opiate-like receptors, on immune cells and indirectly by binding to receptors on CNS cells. Studies conducted in vitro with opiate-treated immune cells demonstrated receptor-mediated reduced phagocytosis, chemotaxis and cytokine and chemokine production. These effects are linked to modulation of host resistance to bacterial, protozoan, viral and fungal infections using animal models, cell lines and primary cells. 

Figure 3. Proposed model for the action of opiates and opioid peptides on glyco-syltransferase activity. It is postulated that receptors for both opiates and neurotransmitters are linked to adenylate cyclase by a guanylnucleotide regulatory protein (GNRP). The presence of opiates or opioid peptides inactivates the cyclase, which normally activates a protein kinase-glycosyltransferase system, thereby initiating...

Pharmacological studies with selective agonists have shown that opioid control of intestinal electrolyte transport is predominantly mediated by delta opioid receptors [58], while the gastrointestinal propulsion is under the control of mu receptors [59,60]. The antidiarrheal effects of NEP inhibitors, such as acetorphan, the prodrug of thiorphan, have been compared to those of an opiate agonist, loperamide, in a model of castor oil-induced diarrhea in rats. When administered peripherally, they produced a delayed onset of diarrhea with no reduction in the gastrointestinal transit [61,62], as is commonly observed with loperamide [63],... 

Molecular Model for an Anionic Opiate p,-Receptor—Affinity and Activation of Morphine Conformers. 

Enkephalins are pentapeptides that bind to opiate receptors. In the gut, enkephalins promote the absorption of sodium, chloride and water (Dobbins et al 1980). Racecadotril is an oral enkephalinase inhibitor used in France and the Philippines for the treatment of acute diarrhea. It prevents the degradation of endogenous opioids (enkephalins) and thus promotes absorption of water and electrolytes from the intestinal lumen (Matheson Noble 2000). Studies have demonstrated the efficacy of racecadotril in two models of hypersecretory diarrhea infusion of cholera toxin and castor oil induced diarrhea. Moreover, unlike loperamide, racecadotril did not prolong transit time in the small intestine or colon. Further experiments have shown that racecadotril does not promote bacterial overgrowth in the small intestine (Duval-Iflah et al 1999). There are no reports on the use of racecadotril in horses. 

Opiate narcotics are thought to act at specific receptors in the brain since they exhibit stereospecific binding (1) and have been shown by fluorescence techniques to be localized at discrete regions in the central nervous system (2). While much effort has been made to isolate and characterize the opiate receptor C3), relatively little detailed information exists about the nature of the opiate binding site. Some investigators describe the receptor as a membrane bound protein or proteo-lipid (4) while others have used nerve cell components such as cerebroside sulfate or phosphatidyl inositol as models for the opiate receptor (5). 

With the exception of the cyclopropylmetbane, the main discrepancy is the relatively large energy calculated for the 2,3 - dimethylfuran. The stabilization energies of the AMS complexes calculated by the empirical method correlate more with the measured affinities and antagonist potencies than those for the AMP complexes. Additionally, more stable complexes with AMS are found by the empirical method than by the PCILO method. Taken together, the results of both methods indicate that either the phosphate or sulfate anion is a reasonable model for the anionic opiate receptor site. 

In this study both the PCILO and empirical energy methods were used to characterize intermolecular interactions of typical N-substituents of rigid opiates with model anionic receptor sites. Ammonium methylphosphate (AMP) and ammonium methylsulfate (AMS) were used as model anionic receptor sites. Interaction energies of eight compounds which, as N-substituents. modulate different antagonist/agonist potencies... 

Feinberg AP, Creese I, Snyder SH (1976) The opiate receptor a model explaining structure-activity relationships of opiate agonists ad antagonists. Proc Natl Acad Sci USA 73 4215-4219... 

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