Inverse Agonists

An inverse agonist binds to the same receptor as a classical agonist and produces a response, but the response is in the opposite direction to that produced by the classical agonist [78]. Presumably, the receptor changes its conformation in such a way that a qualitatively different type of response is produced. Certain compounds, like ethyl P-carboline-3-carboxylate (P-CCE), have been proposed to be inverse agonists of the benzodiazepine receptor. These compounds inhibit the interaction of endogenous GABA with its receptor, thereby decreasing chloride entry into the neuron. The proanxiety effect of P-CCE on the functional level parallels these proposed receptor related interactions, while the classical agonists, the benzodiazepines, exert an antianxiety effect. Furthermore, P-CCE has proconvulsant, while the benzodiazepines have anticonvulsant properties.

Figure 9. Two-state model of drug-receptor interaction. According to this model, the receptor exists in two interconvertible states, R1, an inactive state and R2, an active state. Drugs (D) can interact with either state. A full agonist will bind selectively to R2, shifting the equilibrium to the R2 state, the active conformation, producing a pharmacological response. A partial agonist will bind to both states but will have a higher affinity for R2, producing only a small shift in equilibrium to the active form. Thus, the maximal effect of a high dose of partial agonist would be limited. An inverse agonist will have a higher affinity for the inactive R1 state, causing a shift in equilibrium to the inactive conformation; therefore, the effect produced by the inverse agonist may be opposite to that of the agonist.

Figure 9. Two-state model of drug-receptor interaction. According to this model, the receptor exists in two interconvertible states, R1, an inactive state and R2, an active state. Drugs (D) can interact with either state. A full agonist will bind selectively to R2, shifting the equilibrium to the R2 state, the active conformation, producing a pharmacological response. A partial agonist will bind to both states but will have a higher affinity for R2, producing only a small shift in equilibrium to the active form. Thus, the maximal effect of a high dose of partial agonist would be limited. An inverse agonist will have a higher affinity for the inactive R1 state, causing a shift in equilibrium to the inactive conformation; therefore, the effect produced by the inverse agonist may be opposite to that of the agonist.

The interactions of full agonists, partial agonists and inverse agonists with receptors have also been explained using a dynamic model of the receptor (Figure 9) [47-79]. That is, the receptor is postulated as existing in two important interconvertible states, an active state (R2) and a resting state (R1). The conversion between the two states is regulated by an equilibrium constant (K). In the absence of agonist, most of the receptors are in the resting state. A full agonist binds preferentially to the active form of the receptor (R2), which would shift the equilibrium to increase the proportion of receptors in the active form. Assuming no spare receptors, at saturating concentrations of agonist, 100% of the receptors would be in the active form, producing a maximum response. A partial agonist would bind to both receptor forms, R2 and R1, but has a higher affinity for the active form (R2). When the receptors are saturated with the partial agonist, a smaller proportion of the receptors would be in the active form compared to that occurring with a full agonist. The binding of the partial agonist to the R1 form would limit the amount of molecules formed and consequently, the maximal response that can be produced. In contrast to an agonist, an antagonist would bind equally well to both forms of the receptor, resulting in no change in the relative proportion of inactive and active forms of the receptors (the ratio of R2/R1 remains the same). The antagonist will, therefore, not produce an agonist action but will block the ability of an agonist to bind to either form of the receptor. An inverse agonist would have a higher affinity for the receptor in the resting state (R1) and shift the equilibrium toward R1. As a result, there would be an increase in the proportion of the receptors present in the state, which would produce effects that are opposite to those produced by an agonist.

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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