Update on GPCR-based targets for the development of novel antidepressants

Abstract

Traditional antidepressants largely interfere with monoaminergic transport or degradation systems, taking several weeks to have their therapeutic actions. Moreover, a large proportion of depressed patients are resistant to these therapies. Several atypical antidepressants have been developed which interact with G protein coupled receptors (GPCRs) instead, as direct targeting of receptors may achieve more efficacious and faster antidepressant actions. The focus of this review is to provide an update on how distinct GPCRs mediate antidepressant actions and discuss recent insights into how GPCRs regulate the pathophysiology of Major Depressive Disorder (MDD). We also discuss the therapeutic potential of novel GPCR targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles. Finally, we highlight recent advances in understanding GPCR pharmacology and structure, and how they may provide new avenues for drug development.

Fig. 1. Receptors that are targeted by established treatments in brain regions involved in MDD.

In the center, it is depicted the human brain together with different brain areas that are involved in the symptomatology of MDD. Each circle panel shows the neuronal types that have been found to affect depressive-like behavior together with the receptors that they express. GABA neurons/terminals: gray, glutamate neurons/terminals: blue, DA neurons/terminals: pink, 5-HT neurons/terminals: cyan, NE neurons/terminals: yellow, cholinergic neurons/terminals: orange. VTA ventral tegmental area, mPFC medial prefrontal cortex, LHA lateral hypothalamic area, NAc nucleus accumbens, DR dorsal raphe, LHb lateral habenula, RMTg rostromedial tegmentum, ACC anterior cingulate cortex, BA25 Brodmann area 25, HF hippocampal formation, Amy amygdala, dMSN direct medium spiny neuron, iMSN indirect medium spiny neuron, CIN cholinergic interneuron, GIN GABAergic interneuron, Py pyramidal, Glu glutamate, DA dopamine, 5-HT serotonin, 5-HTT serotonin transporter, NET norepinephrine transporter, MAOA/B monoamine oxidase A/B, TMS transcranial magnetic stimulation.

Fig. 2. Novel avenues of receptor targeting.

Starting from left: A ligand which recognizes a specific dimer pair of receptors with a GABA_B receptor as an example. Here, the extracellular region of GABA_B1 binds the ligand and the second (GABA_B2) transmembrane receptor recruits G-proteins for downstream signaling cascades. Biased ligands can be used to favor signaling along one signaling pathway while avoiding the other. Similarly, allosteric modulators may be used to regulate the endogenous agonist response, either in an excitatory (PAM) or inhibitory (NAM) fashion. Likewise, antibody-based ligands have been demonstrated both in nature and in recent pharmacological screens to exert excellent target specificity. Specific receptor populations may also be targeted by focusing on intracellular targets such as with the neurokinin-1 receptor. Lastly, the development of rationally designed molecules targeting both a GPCR and an intracellular enzyme may modulate two distinct cellular processes inducing a greater therapeutic response form the drug.

Fig. 3. Novel GPCR-based therapeutical strategies in brain regions involved in MDD.

In the center, it is depicted the human brain together with different brain areas that are involved in the symptomatology of MDD. Each circle panel shows the neuronal types that have been found to affect depressive-like behavior together with the receptors that they express. GABA neurons/terminals: gray, glutamate neurons/terminals: blue, DA neurons/terminals: pink, 5-HT neurons/terminals: cyan, NE neurons/terminals: yellow, cholinergic neurons/terminals: orange. VTA ventral tegmental area, mPFC medial prefrontal cortex, LHA lateral hypothalamic area, NAc nucleus accumbens, DR dorsal raphe, LHb lateral habenula, RMTg rostromedial tegmentum, ACC anterior cingulate cortex, BA25 Brodmann area 25, HF hippocampal formation, Amy amygdala, dMSN direct medium spiny neuron, iMSN indirect medium spiny neuron, CIN cholinergic interneuron, GIN GABAergic interneuron, Py pyramidal, Glu glutamate, DA dopamine, 5-HT serotonin, 5-HTT serotonin transporter, NET norepinephrine transporter, MAOA/B monoamine oxidase A/B. DREADD designer receptors exclusively activated by designer drugs, DBS deep brain stimulation.

Fig. 4. Orphan GPCRs expressed in brain regions involved in MDD.

In the center, it is depicted the human brain together with different brain areas that are involved in the symptomatology of MDD. Each circle panel shows the neuronal types that have been found to affect depressive-like behavior together with the receptors that they express. GABA neurons/terminals: gray, glutamate neurons/terminals: blue, DA neurons/terminals: pink, 5-HT neurons/terminals: cyan, NE neurons/terminals: yellow, cholinergic neurons/terminals: orange. VTA ventral tegmental area, mPFC medial prefrontal cortex, LHA lateral hypothalamic area, NAc nucleus accumbens, DR dorsal raphe, LHb lateral habenula, RMTg rostromedial tegmentum, ACC anterior cingulate cortex, HF hippocampal formation, Amy amygdala, dMSN direct medium spiny neuron, iMSN indirect medium spiny neuron, CIN cholinergic interneuron, GIN GABAergic interneuron, Py pyramidal, Glu glutamate, DA dopamine, 5-HT serotonin.