T antagonist

Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

A large number of thyroid hormone analogues have been tested for this effect (6). Among others, i-T (3) and 3,3 -T2 (5) and their propionic acid side-chain analogues decrease oxygen consumption at molar ratios of 50—200 1 of T. Nevertheless, no potent or clinically usehil peripheral antagonists have been found. 

H. Fujimoto, I. Nishino, K. Ueno and T. Umeda, Determination of the enantiomers of a new 1,4-dihydropyridine calcium antagonist in dog plasma achiral / chiral coupled high performance liquid cliromatography with electrochemical detection , 7. Pharm. Sci. 82 319-322(1993). 

Costa, T., and Herz, A. (1989). Antagonists with negative intrinsic activity at 6-opioid receptors coupled to GTP-binding proteins. Proc. Natl. Acad. Sci. U.S.A. 86 7321-7325. 

Equation 6.2 can be evaluated in a number of temporal situations. Thus, if there is adequate time for reequilibration of agonist, antagonist, and receptors true competition between agonist and antagonist for receptors will result. Under these circumstances, the equation for agonist occupancy in the presence of antagonist can be evaluated by setting t kj1 in Equation 6.2 to yield... 

FIGURE 6.17 Fitting of data to models, (a) Concentration response curves obtained to an agonist in the absence (circles) and presence of an antagonist at concentrations 3 jiM (triangles) and 30 j.lM (diamonds), (b) Data fit to model for insurmountable orthosteric antagonism (Equation 6.31) with Emax = 1, Ka = 1 pM, t = 30 and KB = 1 pM. 

FIGURE 6.19 Use of the clextral displacement produced by an insurmountable antagonist to estimate dose ratios and subsequent pA2 values. Response according to model for orthosteric noncompetitive blockade (Equation 6.31 with Emax = 1, t = 3, Ka = 0.3 pM, Kb = 1 pM) for 1 pM and 3 pM antagonist. Dose ratios measured at response = 0.24 for 1 pM antagonist and response = 0.15 for 3pM antagonist. Resulting pA2 values are close estimates of the true pKB (6.0) as modified by the [A]/Ka term (see Equation 6.37). 

As discussed in Chapter 7, antagonists may bind to a separate loci on the receptor and thereby allosterically modify the affinity of the receptor for the agonist. The maximal change in the agonist affinity is denoted by a term a. It is useful to distinguish allosteric effects in terms of whether the modulator affects signaling and affinity or just affinity. In the latter situation, the modulator produces parallel shifts to the right of the concentration response curve up to a maximal point. This is discussed in Section 7.4.1 (t, = 1). Under these circumstances, the curve for... 

In the course of pharmacological experiments, a frequent question is Does the experimental system return expected (standard) values for drugs With the obvious caveat that standard values are only a sample of the population that have been repeatedly attained under a variety of circumstances (different systems, different laboratories, different investigators), there is a useful statistical test that can provide a value of probability that a set of values agree or do not agree with an accepted standard value. Assume that four replicate estimates of an antagonist affinity are made (pKb values) to yield a mean value (see Table 11.14). A value of t can be calculated that can give the estimate probability that the mean value differs from a known value with the formula... 

Another frequent question asked considers whether the mean of a value measured by two separate methods differs significantly. For example, does the mean pKB value of an antagonist measured in a binding experiment differ significantly from its affinity as an antagonist of agonist function The value of t for the comparison of the mean values xml and xm2 can be calculated with the following equation ... 

Kenakin, T. P., and Beek, D. (1981). The measurement of antagonist potency and the importance of selective inhibition of agonist uptake processes. J. Pharmacol. Exp. Ther. 219 112-120. 

Ogren SO, Koteeva E, Hokfelt T et al (2006) Galanin receptor antagonists a potential novel pharmacological treatment for mood disorders. CNS Drugs 20 633-654... 

IFN- 3 reduces the induction by inflammatory cytokines of adhesion molecules and of MHC class I and II complex on endothelial cells, a process preceding attachment and transendothelial migration of T-cells. These anti-inflammatory effects of IFN- 3 exemplify antagonistic actions of type I and type IIIFN. There is, indeed, much clinical evidence for the involvement of IFN-y in inflammatory processes - through activation of iNOS and subsequent secretion of NO - leading to the establishment of autoimmune diseases as for instance in rheumatoid arthritis. 

Tissue-specific Agonists/Antagonists Tissue-type Plasminogen Activator T-kinin (Ile-Ser-Bradykinin)... 

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