During the last half a century, a lot of psychoactive agents have been developed
and utilized as therapeutic drugs for mental disorders such as schizophrenia, mood disorders,
anxiety disorders, and dementia. Based on the major target illnesses or symptoms, they have
been classified into antipsychotics, antidepressants, mood stabilizers, anxiolytics, hypnotics,
and nootropics. From a pharmacological point of view, it is well established that most of
these psychotropic drugs alter neural transmission via classical neurotransmitters, e.g.,
dopamine, serotonin (5-HT), norepinephrine (NE), glutamate, γ-aminobutyric acid (GABA),
and acetylcholine, all of which are implicated in the maintenance and control of higher brain
function and human behavior. One major molecular target of these psychotropic drugs is a G
protein-coupled receptor (GPCR), at which the neurotransmitter is specifically bound. In
most cases, the psychotropic drugs behave as antagonists at the GPCR. For instance, all
classical antipsychotics are antagonists of dopamine D2 receptors. The recent approval and
great success of aripiprazole (a partial dopamine D2 agonist) as an effective antipsychotic
drug in many countries, has paved the way for the concept that some GPCR agonists have
the potential to treat psychiatric illnesses. Interestingly, the prototypic atypical antipsychotic
clozapine (or its active metabolite N-desmethylclozapine) behaves as an agonist at several
GPCRs. It is also well known that 5-HT1A receptor agonists, such as buspirone and
tandospirone, are efficacious anxiolytics. Another major progress in psychopharmacology in
recent years is the recognition of multiple allosteric sites for many GPCRs, and many novel
allosteric modulators of GPCRs have been synthesized. Though still preliminary, many
studies have indicated that these allosteric modulators are promising as novel effective
psychotropic drugs. In this chapter, the author will provide an update of the recent
development of psychoactive agents that act as agonists or allosteric modulators at several
GPCR subtypes, which are potentially useful as therapeutic drugs for mental disorders.
Keywords: Antipsychotic, antidepressant, anxiolytic, G protein-coupled receptor
(GPCR), agonist, intrinsic activity, antagonist, allosteric modulator, dopamine,
serotonin (5-HT), acetylcholine, glutamate.
