Receptors specificity

The second application of the CFTI protocol is the evaluation of the free energy differences between four states of the linear form of the opioid peptide DPDPE in solution. Our primary result is the determination of the free energy differences between the representative stable structures j3c and Pe and the cyclic-like conformer Cyc of linear DPDPE in aqueous solution. These free energy differences, 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. The predicted low population of the cyclic-like structure, which is presumably the biologically active conformer, agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide. 

Biochemically, most quaternary ammonium compounds function as receptor-specific mediators. Because of their hydrophilic nature, small molecule quaternaries caimot penetrate the alkyl region of bdayer membranes and must activate receptors located at the cell surface. Quaternary ammonium compounds also function biochemically as messengers, which are generated at the inner surface of a plasma membrane or in a cytoplasm in response to a signal. They may also be transferred through the membrane by an active transport system. 

The ability to reduce stimulus-response mechanisms to single mono tonic functions allows relative cellular response to yield receptor-specific drug parameters. 

By utilizing complete dose-response curves, the method devised by Barlow, Scott, and Stephenson [9] can be used to measure the affinity of a partial agonist. Using null procedures, the effects of stimulus-response mechanisms are neutralized and receptor-specific effects of agonists are isolated. This method, based on classical or operational receptor theory, depends on the concept of equiactive concentrations of drug. Under these circumstances, receptor stimuli can be equated since it is assumed that equal responses emanate from equal stimuli in any given system. An example of this procedure is given in Section 12.2.1. 

Equilibrium (dissociation) constant, reciprocal of the association constant and affinity characterizes the binding of a molecule to a receptor. Specifically, it is the ratio of the rate of offset of the molecule away from the receptor divided by the rate of onset toward the receptor. It also is a molar concentration that binds to 50% of the receptor population. 

The dopamine system constitutes the cellular and biochemical network that is involved in the synthesis, release, and response to dopamine. In general, this involves cells that express significant levels of tyrosine hydroxylase (TH) and limited amounts of dopamine (3-hydioxylase [1]. Dopamine-responsive cells express receptors specifically activated by this neurotransmitter, which are known as dopamine Dl, D2, D3, D4, and D5 receptors [2, 3]. 

Parrill AL, Sardar VM, Yuan H (2004) Sphingosine 1-phosphate and lysophosphatidic acid receptors agonist and antagonist binding and progress toward development of receptor-specific ligands. Semin Cell Dev Biol 15 467-476... 

Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by a receptor specific for apo E (Figure 25-3), and both the LDL (apo B-lOO, E) receptor and the LRP (LDL receptor-related protein)... 

Vergote D, Butler GS, Ooms M, Cox JH, Silva C, Hollenberg MD, Jhamandas JH, Overall CM, Power C (2006) Proteolytic processing of SDF-lalpha reveals a change in receptor specificity mediating HIV-associated neurodegeneration. Proc Nad Acad Sci USA 103(50) 19182-19187 von Giesen HJ, Roller H, Theisen A, Arendt G (2002) Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HlV-1-infected patients. J Acquir Immune Defic Syndr 29(4) 363-367... 

J.E. Leysen, Review of neuroleptic receptors specificity and multiplicity of in-vitro binding related to pharmacological activity. In Clinical pharmacology in psychiatry (E. Usdin, S. Dahl, L.F. Gram and O. Lingjaerde, Eds.). MacMillan, London, 1982, pp. 35-62. 

Opioid peptides, 17 (1980) 1 receptor antagonists, 35 (1998) 83 receptor-specific analogues, 28 (1991)... 

Generic Name (Trade Name) Mechanism of Action and Receptor Specificity Dosing... 

Cohen-Hillel E, Yron I, Meshel T, Soria G, Attal H, Ben-Baruch A. CXCL8-induced FAK phosphorylation via CXCR1 and CXCR2 Cytoskeleton- and integrin-related mechanisms converge with FAK regulatory pathways in a receptor-specific manner. Cytokine 2006 33 1-16. 

Agace WW, Roberts Al, Wu L, Greineder C, Ebert EC, Parker CM. Human intestinal lamina propria and intraepithelial lymphocytes express receptors specific for chemokines induced by inflammation. Eur J Immunol 2000 30 819-826. 

Loetscher M, Gerber B, Loetscher P, et al. Chemokine receptor specific for IP10 and mig structure, function, and expression in activated T-lymphocytes. J Exp Med 1996 184(3) 963-969. 

Hruby YJ, Gehring CA. Recent developments in the design of receptor specific opioid peptides. Med Res Rev 1989 9 343-401. 

Schiller PW. Development of receptor specific opioid peptide analogs. In Ellis GP, West BG, eds. Progress in Medicinal Chemistry. Vol. 28. Amsterdam Elsevier, 1991 301-340. 

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