Affinity ratio

Table 11.4. Clozapine, haloperidol and risperidone comparative values for in vitro receptor affinity ratio and in vivo receptor occupancy.

Drug D4 D2 affinity ratio 5-HT2A D2 affinity ratio D2-like occupancy (%) 5-HT2 occupancy (%)... 

Affinity ratios represent the mean of three values, calculated from published K or Kd data (data from Seeman et al., 1997 Strange, 1998 Kerwin, 2000). Occupancy of D2-like (basal ganglia) and 5-HT2 (neocortex) receptors was assessed using PET or SPECT (data from Waddington and Casey, 2000). 

According to X-ray and neutron diffraction structures [3, 4] the binding of CO to the heme leads to a bent FeCO unit. The Fe-C-O angle is, however, found to be linear in synthetic models of the protein (hiomimetic molecules). Because of this, it was originally thought that the FeCO distortion was responsible for the well known discrimination of the protein against CO - the affinity ratio C0/02 is lower in the protein than in biomimetic systems [1]. In... 

Dopamine and 5-HT receptor blockade d-HTja/Dj affinity ratio 8 1... 

All the novel antipsychotics have an enhanced 5-HT2 to D2 receptor affinity ratio and a lower, though not negligible, affinity for the D 2 receptor. 

Of the clinically tested new antipsychotics, ziprasidone has the highest 5-HT2A/D2 receptor-affinity ratio. Ziprasidone is an antagonist at the a -adrenoreceptor, but its affinity is half that of its D 2 affinity. In addition, compared with its affinity for D 2 and 5-HT2A receptors, ziprasidone has a relatively low affinity for histamine receptors (pKJ = 7.33). In vitro, ziprasidone is a moderately potent inhibitor of neuronal reuptake of norepinephrine, serotonin, and, to a lesser extent, dopamine. This property is shared with some antidepressants, and contrasts with risperidone, which is inactive at all three monoamine uptake sites. 

The formation of an unstable,covalent phosphoryl-AChE conjugate is evidently accompanied by a non-covalent reversible complex (Michaelis complex) between AChE and TDPI (AChE TDPI). Although TMPH (K. = 0.25 pM) was found to be 100 fold more powerful than TDPI (K = 0.02 mM) in terms of concentration required to achieve similar amount of Michaelis complex, TDPI provided better protection of AChE against irreversible phosphorylation by II. In this set of experiments, the efficiency of TDPI and TMPH were compared on the basis of equal concentration/affinity ratio were I/Kj = 10. 

Fig. 1.20 The progressive change from the D2/D3 receptor nonselective antagonists to the highly D3-selective compound Do 897 [43], The numbers in parentheses indicate the D2/D3 affinity ratio.

Ketanserin appears to act principally to block serotonin vasoconstrictor (subtype 5-HTj) receptors but also has significant a-adrenoceptor blocking activity (its affinity ratio for the two receptors is 1 5). The latter explains its hypotensive action and use in Raynaud s disease. It is not available in many countries and offers no advantages over pure a-blockers such as doxazosin. 

This approach has the possible advantage over using a combination of two inhibitors, that it eliminates all the pharmacokinetic variables and synchronizes the inhibitory action at the two enzyme sites. However, there is a competition between the two enzymes for the inhibitor, since each molecule of the latter can bind only to one enzyme therefore, the relative extent of inhibition of the two metabolic reaction steps depends on the relative affinities (ratio of the Kj values) of the inhibitor for the two enzymes. This, of course, is determined by the structure of the inhibitor, and it should be amenable to change via structural modifications (e.g., by providing 71 with a hydroxyalkyl side chain and thus making it more closely similar in structure to riboflavin and more antagonistic to it). Although this approach has inherent limitations in scope, its further exploration appears to be of interest. 

Ziprasidone has the highest 5-HT2a D2 affinity ratio of any of the currently available antipsychotics. It is also a potent 5-HTia agonist. ... 

The debate about factors controlling discrimination between CO vs. O2 affinities for deoxyMb/Hb has been particularly lively. The key observation spawning this debate is that synthetic pentacoordinate ferrous hemes in solution bind CO approximately 100,000 times more strongly than O2, whereas Hb and Mb bind CO only about 100 times more strongly than 02. This lowering of the CO/O2 affinity ratio by Hb and Mb compared to synthetic hemes, while insufficient to prevent the well-known toxicity of inhaled CO, does minimize interference with... 

Table III. Comparison of the Affinity Ratios for R- and S-Phenylisopropyl adenosine (PIA) Derived from Both Radioligand Binding Assays and Functional Measures of Aj Adenosine Receptor Activation...

Oxygen-binding to tetra(2, 4, 6 -triphenyl)porphinatoiron was reported by Suslick et al. This porphinatoiron has two pockets formed by phenyl substitutes on both faces of the porphyrin. The seous molecule-binding affinity was studi l in benzene solution The pocket structure minimized the solvation of the coordinatol oxygen and of CO and influenced the affinity ratio of oxygen/CO. But the life-time of the oxygen adduct was not enhanced in comparison with that of /. 

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