Rank order of potency

Division of the receptors in the adrenergic nervous system into two classes (a and P) was proposed in 1948 (39) when a difference in the rank order of potency of epinephrine (1, R = CH ), norephinephrine (1, R = H), and isoproterenol [7683-59-2], C H yNO, (1, R = CH(CH3)2) was noted to depend on the organ examined. Eurther subdivision into groups P2 proposed in 1967 (40). Both types of P-adrenoceptors are found throughout the... 

If the behavioral activity of PCP is related to its block of pre-synaptic K channels (Albuquerque et al. 1981 Albuquerque et al. 1983 Blaustein and Ickowicz 1983), PCP-like analogues should block these same K channels with a rank order of potency that parallels their relative in vi vo psychotomimetic activity. One of the most behavioral ly potent PCP-like agents is TCP (1 -[1 -(2 -thienyl)-cyclohexyl] piperidine) (Shannon 1983). Figure 4 illustrates the dose-response curves for the block of components S and T by this drug. The data indicate that TCP is a more potent blocker of Sv than is PCP (figure 2). TCP blocked component T only at high concentrations (>10 5M), and in this respect was approximately equivalent in potency to PCP (figure 2). 

The binding of 3H-PCP to whole brain homogenates was saturable and completely displaced by unlabeled PCP at a concentration of 10-5 M. PCP-related compounds displaced 3H-PCP and varied in potency. Although this work is still in progress, preliminary results indicate a rank order of potency for the displacement of 3H-PCP from its receptor similar to those reported for effects on EEG, rotarod performance, and SLA. 

On comparing the activities of the five compounds for which numerical estimates are available in all three assays (synephrine, octopamine, phenylethanolamine, norepinephrine and tyramine) the rank orders of potency in the three systems are Crayfish, 1,2,3t4,5 Cockroach, 2,1,3,4,5 Locust 1,2,3t5,4. This indicates a basic similarity in the responses of these preparations. In each case it was found that ring hydroxylation of the phenylethylamine nucleus was not essential for activity, although p-hydroxylation does yield the best activity. This is particularly evident in the crayfish study where a-MAMBA (a-methylaminomethyl benzyl alcohol), the analog of synephrine which lacks ring substitution, was one of the most active compounds tested, and 3-phenylethanolamine, the corresponding analog of OA, is almost as active as OA. The base compound for this series, phenylethylamine, also shows appreciable activity, but only in the crayfish assay. 

EGb inhibits the uptake of [3H]norepinephrine ([3H]NE) and [3H]dopamine and [3H]5-hydroxytryptamine ([3H]5-HT) into in vitro synaptosomes prepared from the striatum and cortex in a concentration-dependent manner. The rank order of potency for the inhibition of amine uptake is NE > dopamine > 5-HT [173]. Similar results were obtained by Ramassamy et al. [174]. These workers showed that EGb decreased the specific uptakes of [3H]dopamine, [3H]5-HT and [3H]choline by synaptosomes prepared from the striatum of mice in a concentration-dependent manner. The IC,0 values were 637 pg/rol for [3H]dopamine uptake, 803 pg/ml for [3H]5-HT uptake, >2000 pg/ml for [3H]choline uptake. However, they concluded that the inhibition of amine uptake caused by EGb appears to be non-specific, since EGb also prevents the specific binding of the dopamine uptake inhibitor [3H]GBR12783 to membranes prepared from striatum. 

Concerning human studies, only three reports have been reported (for review see Burnstock et al., 2000). Bleehen and Keele (1977) reported observations on the algogenic actions of adenosine compounds on blister base preparations. Coutts et al. (1981) injected ATP, ADP, AMP, adenosine, adenine and inosine intradermally. The area of erythema induced by the injection was delineated at 30 s. and again after a further 4.5 min when the size of the response was maximal. ATP, ADP and AMP evoked weal and flare responses in the skin in a dose-dependent manner. The rank order of potency was ATP > ADP > AMP other metabolites were apparently inactive. Injections of ATP and high doses of ADP produced a sensation of persistent pain. 

Blockade of the 5-HT7 receptor has been shown to reduce epileptic activity in animal models. Audiogenic seizures induced in DBA/2J mice could be prevented by drugs in a rank order of potency corresponding to their affinity for the 5-HT7 receptor (95). The selective 5-HT7 receptor antagonist SB-258719 has been shown to reduce epileptic activity in an animal model for absence epilepsy, the WAG/Rij rat (65). It is believed to do so by modulating the pacemaker current Ih within the thalamus (96,97). The 5-HT7 receptor has been demonstrated to mediate depolarization within the anterodorsal thalamus by increasing lh through a cAMP-dependent, PKA-independent mechanism (96,97). 

The affinities (Tab. 13.1) and rank order of affinities (Tab. 13.2) of clozapine-type compounds clearly show that their primary receptor targets are serotonin (excep. 5-HTj), histamine Hj and adrenergic receptors, followed by dopamine receptors. Whilst clozapine and olanzapine seem to have some similarities in their overall receptor profile, quetiapine differs from them not only in the significantly lower absolute affinity values but also in the rank order of potencies that is, it has the highest affinity for adrenergic alpha-1 and histamine H, receptors followed by 5-HT2A and dopamine receptors. 

In an in vitro study of the effects of the HIV-1 protease inhibitors, ritonavir, indinavir, and saquinavir, which are metabolized by the liver CYP3A4, all three protease inhibitors inhibited methadone demethylation and buprenor-phine dealkylation in rank order of potency ritonavir > indinavir > saquinavir (53). Clinical studies are required to establish the further relevance of these observations. 

It is of equal importance to determine the precision of the measurements. When in-house data on reference compounds are compared to those in the public domain, it is often found that published data might vary considerably between laboratories, ffowever, these data are acceptable if the rank-order of potency was the same between different assay formats and clinical observations are in support of the findings. 

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