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Review
. 2023 Sep;299(9):105176.
doi: 10.1016/j.jbc.2023.105176. Epub 2023 Aug 18.

Molecular insights into GPCR mechanisms for drugs of abuse

Omar B Sanchez-Reyes  1 , Gregory Zilberg  2 , John D McCorvy  3 , Daniel Wacker  4
Affiliations
Review

Molecular insights into GPCR mechanisms for drugs of abuse

Omar B Sanchez-Reyes et al. J Biol Chem. 2023 Sep.

Abstract

Substance abuse is on the rise, and while many people may use illicit drugs mainly due to their rewarding effects, their societal impact can range from severe, as is the case for opioids, to promising, as is the case for psychedelics. Common with all these drugs' mechanisms of action are G protein-coupled receptors (GPCRs), which lie at the center of how these drugs mediate inebriation, lethality, and therapeutic effects. Opioids like fentanyl, cannabinoids like tetrahydrocannabinol, and psychedelics like lysergic acid diethylamide all directly bind to GPCRs to initiate signaling which elicits their physiological actions. We herein review recent structural studies and provide insights into the molecular mechanisms of opioids, cannabinoids, and psychedelics at their respective GPCR subtypes. We further discuss how such mechanistic insights facilitate drug discovery, either toward the development of novel therapies to combat drug abuse or toward harnessing therapeutic potential.

Keywords: GPCR; cannabinoid; drugs of abuse; opioid; pharmacology; serotonin; structure.

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Conflict of interest statement

Conflict of interest D. W. has consulted for Otsuka Pharmaceutical, Longboard Pharmaceuticals and Ocean Bio Ltd on the design of psychedelic-based therapeutics. None of the companies listed herein contributed to the funding or narrative of the manuscript. The other authors declare that they have no conflicts of interest with the contents of this article.

Figures

Figure 1
Figure 1
GPCR activation and signaling.A, schematic of GPCR signaling highlighting different transducers including heterotrimeric G proteins (Gα/Gβ/Gγ), GPCR kinases (GRKs), and β-arrestins (β-Arr). Transducer binding and activation modulates secondary messenger (e.g., cAMP, Ca2+) levels, activates downstream effectors such as extracellular signal-regulated kinase (ERK), proto-oncogene tyrosine-protein kinase Src (Src), or causes receptor internalization. B, superposition of the active (light blue, PDB ID: 3SN6) and inactive state (red, PDB ID: 2RH1) β2-AR structures reveals activation-related conformational changes largely conserved among class A GPCRs. W6.48 located in TM6 connects changes in the ligand-binding site and transducer-binding site. Downward motion of W6.48 is connected to coordinated changes of I3.40 and F6.44 of the P-I-F motif, which links to an outward motion of TM6’s cytoplasmic half. C, schematics illustrating differences in the activation mechanisms of MOR, CB1, and 5-HT2A compared to β2-AR according to structural studies. Observed differences, for instance, comprise order-disorder transitions of intracellular loops, changes in the position of TMs, and key residue switches that relate structural changes between ligand- and transducer-binding sites. 5-HT, 5-hydroxytryptamine; β2-AR, β2-adrenergic receptor; CB, cannabinoid receptor; GPCR, G protein–coupled receptor; IL2, intracellular loop 2; MOR, μ-opioid receptor; TM, transmembrane.
Figure 2
Figure 2
Structures of opioid drugs bound to the μ-opioid receptor.A, overview of the fentanyl-bound MOR-Gi1 signaling complex cryo-EM structure (PDB ID: 8EF5), and chemical structures and close ups of orthosteric-binding pocket bound by morphine (PDB ID: 8EF6), fentanyl (PDB ID: 8EF5), TRV130/oliceridine (PDB ID: 8EFB), and mitragynine pseudoindoxyl (MP) (PDB ID: 7T2G). MOR, Gαi1, Gβ1, and Gγ2 are highlighted in light blue, green, wheat, and magenta, respectively. Top, key side chains and drugs (light brown) are shown as sticks, and hydrogen bonds and ionic bonds are shows as gray dashed lines. B, schematic illustrating differences in the binding poses of the opioids fentanyl and MP, the latter of which extends into a distinct pocket near TM7. MOR, μ-opioid receptor; TM, transmembrane.
Figure 3
Figure 3
Structural insights into the molecular actions of cannabinoid drugs.A, overview of G protein–bound CB1-agonist complex (PDB ID: 6KPG) with the receptor, Gαi1, Gβ1, and Gγ2 highlighted in light blue, green, wheat, and magenta, respectively. Chemical structures and close ups of cannabinoid drugs AM841 (PDB ID: 6KPG) and MDMB-FUBINACA (PDB ID: 6N4B) bound to the CB1 orthosteric pocket, and inset shows chemical structure of THC by comparison. Drugs (magenta) and side chains are shown as sticks, and hydrogen bonds and ionic bonds are indicated by gray dashed lines. B, membrane view of CB1 showing 7TM architecture (light blue) (PDB ID: 5TGZ). Residues of the N terminus are shown in green and bound drug AM6538 is shown in magenta. Zoom-in shows gap in TM1-TM7 interface, which likely serves as the entry pore for hydrophobic CB1 ligands from within the membrane. C, proposed activation of CB1 elucidated by the overlay of inactive state (red, PDB ID: 5TGZ) and G protein–bound (green) active state (light blue, PDB ID: 6KPG) involves inward motion of aromatic residues in TM2, followed by the pairwise motion of F2003.36 and W3566.48, designated as the twin-toggle switch. D, schematic illustrates the L-shape binding mode of cannabinoid drugs, and the reported receptor entry of cannabinoid ligands from the membrane via an opening of the 7TM bundle. 7TM, seven-transmembrane; CB, cannabinoid receptor; THC, tetrahydrocannabinol.
Figure 4
Figure 4
Structural studies of psychedelics and development of novel 5-HT2A agonists.A, overview of the 25CN-NBOH–bound 5-HT2A–Gq signaling complex cryoEM structure (PDB ID: 6WHA), with the receptor, Gαq, Gβ1, and Gγ2 highlighted in light blue, green, wheat, and magenta, respectively. Close ups of 5-HT2A (light blue) and 5-HT2C (purple) orthosteric-binding sites showing binding poses of LSD (PDB ID: 6WGT), lisuride (PDB ID: 7WC7), 25CN-NBOH (PDB ID: 6WHA), and psilocin (PDB ID: 8DPG). Side chains and drugs (yellow) are shown as sticks, and gray dashes indicate hydrogen bonds and ionic interactions. B, extracellular view of the LSD-bound 5-HT2A orthosteric site reveals extracellular lid (green) formed by EL2 that covers the binding site. C, computational structure–guided ligand discovery generates a novel 5-HT2A agonist, (R)-69, whose binding pose was experimentally determined (PDB ID: 7RAN). D, schematic illustrates the distinct binding poses of the chemically related compounds LSD and lisuride that have been proposed to play a role in the distinct pharmacological effects of the drugs. 5-HT, 5-hydroxytryptamine; EL, extracellular loop; LSD, lysergic acid diethylamide.
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