Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs

Abstract

Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents, and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.

Insulin Signaling Deficiency Produces Immobility in Caenorhabditis elegans That Models Diminished Motivation States in Man and Responds to Antidepressants

“…The neurotransmitter and drug concentrations evaluated in these experiments were based on either standard values from the literature or levels found effective for other drugs of the same general class [24,25]. The drug and control plates were allowed to dry and equilibrate for 2-3 h prior to use.…”

Crossing the Worm-Brain Barrier by Using <b><i>Caenorhabditis elegans</i></b> to Explore Fundamentals of Human Psychiatric Illness

“…Simple model organisms, including C. elegans , have proven valuable for investigating mechanisms of action of psychotropic drugs and identification of new targets of these drugs [recently reviewed in [55]]. In fact, it has been both surprising and encouraging that so many drugs originally optimized to treat human psychiatric illness also show potent activity in C. elegans against disease-relevant behaviors.…”

“…C. elegans has already been instrumental for the identification of new targets and signaling pathways affected by CNS drugs [55]. For example, studies of clozapine revealed that it binds to the trace amine-associated receptor TAAR1, which was then implicated in clozapine enhancement of PPI [56].…”

Antipsychotic Drugs Differentially Affect mRNA Expression of Genes Encoding the Neuregulin 1-Downstream ErbB4-PI3K Pathway

“…Apart from blocking the receptors traditionally explaining the antipsychotic action of atypical APDs, CLO possesses an affinity for the full range of receptors: serotonin, dopamine, adrenergic, cholinergic and histaminic [4] , as well as ion channels, transporters and other molecules [4,5] . CLO also differentially changes the expression of numerous genes [6,7] .…”