Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?

Abstract

Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D(2) receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D(2) and 5-HT(2A) antagonists, and those that also bind with modest affinity to D(2), 5-HT(2A), and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D(2) partial agonism or D(2) functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D(2) functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D(2) antagonists.

Figure 1

Structures of representative first generation (typical) drugs. The top row is representative of the many diverse phenothiazines that have been marketed, whereas the bottom row shows the widely used butyrophenone haloperidol and a representative thioxanthene, flupenthixol.

Figure 2

Structures of representative second generation drugs. The top row shows clozapine and two compounds in which the structural similarity can be easily seen. The bottom row shows the structure of ziprasidone, a fourth compound with “rich” pharmacology, as well as risperidone, the prototype of the “DA-5-HT potent dual antagonist.”

Figure 3

Cartoon illustrating how the proposed D₂ dopamine partial agonist mechanism works in third generation antipsychotics. Left column: mesolimbic dopaminergic transmission. Right column: Prefrontal cortical dopaminergic transmission. Broad dotted line: “normal” dopamine activity; solid dark box: Abnormal transmission in schizophrenia; Solid sigmoidal line: actions of partial agonist alone. Dotted sigmoidal line: actions of partial agonist in the presence of endogenous concentrations of dopamine.

Figure 4

Cartoon illustrating how functional selectivity at a single receptor might lead to an altered balance of therapeutic and side effects [Adapted from 140]. In this example, the “typical” ligand [Left panel] is an agonist that activates two signaling pathways via single receptor. One of these pathways is specifically linked to a therapeutic effect, the other to a side effect. The “functionally selective” ligand [right panel] fully activates only the pathway linked to the therapeutic effect, thereby decreasing side effects mediated by this single receptor.

Figure 5

Structures of some of the mechanistically interesting compounds.