OPEN Foundation

B. Roth

Structure of a Hallucinogen-Activated Gq-Coupled 5-HT 2A Serotonin Receptor

Abstract

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

Kim, K., Che, T., Panova, O., DiBerto, J. F., Lyu, J., Krumm, B. E., Wacker, D., Robertson, M. J., Seven, A. B., Nichols, D. E., Shoichet, B. K., Skiniotis, G., & Roth, B. L. (2020). Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell, 182(6), 1574–1588.e19. https://doi.org/10.1016/j.cell.2020.08.024

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Psilocybin for depression and anxiety associated with life-threatening illnesses

Abstract

Life-threatening and terminal illnesses are accompanied by substantial stressors that encumber both patients and their families. Faced with a life-threatening diagnosis such as late-stage cancer, these factors can compound the existential crisis of impending mortality and produce or exacerbate major depressive and anxiety symptoms (Silverstone, 1990; Vergo et al., 2016). Addressing depression and anxiety in the unique context of life-threatening illnesses has been a significant problem for palliative psychiatric care. In this regard, two recent studies suggest that the one-time use of the naturally derived psychoactive compound psilocybin could have the potential to alleviate these symptoms for up to six months.

McCorvy, J. D., Olsen, R. H., & Roth, B. L. (2016). Psilocybin for depression and anxiety associated with life-threatening illnesses. Journal of psychopharmacology (Oxford, England), 30(12), 1209. 10.1177/0269881116675771
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Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor

Abstract

The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand–receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure–activity relationships, and previous salvinorin A–KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.

Polepally, P. R., Setola, V., Vardy, E., Roth, B. L., Mosier, P. D., & Zjawiony, J. (2014). Michael Acceptor Approach to the Design of New Salvinorin A-Based High Affinity Ligands to the Kappa-Opioid Receptor. Planta Medica, 78(5), 818-829. https://dx.doi.org/10.1016/j.ejmech.2014.07.077
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The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

Abstract

In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as ‘designer drugs’ and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

Roth, B. L., Gibbons, S., Arunotayanun, W., Huang, X. P., Setola, V., Treble, R., & Iversen, L. (2013). The ketamine analogue methoxetamine and 3-and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor. PLoS One, 8(3), e59334. http://dx.doi.org/10.1371%2Fjournal.pone.0059334
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Screening the receptorome for plant-based psychoactive compounds

Abstract

Throughout time, humans have used psychoactive plants and plant-derived products for spiritual, therapeutic and recreational purposes. Furthermore, the investigation of psychoactive plants such as Cannabis sativa (marijuana), Nicotiana tabacum (tobacco) and analogues of psychoactive plant derivatives such as lysergic acid diethylamide (LSD) have provided insight into our understanding of neurochemical processes and diseases of the CNS. Currently, many of these compounds are being used to treat a variety of diseases, such as depression and anxiety in the case of Piper methysticum Kava Kava (Martin et al., 2002; Singh and Singh, 2002). G-protein coupled receptors (GPCRs) are the most common molecular target for both psychoactive drugs and pharmaceuticals. The “receptorome” (that portion of the genome encoding ligand reception) encompasses more than 8% of the human genome (Roth et al., 2004) and as such provides a large number of possible targets for psychoactive drug interactions. A systematic, comprehensive study is necessary to identify novel active psychoactive plant-based compounds and the molecular targets of known compounds. Herein we describe the development of a high throughput system (HTS) to screen psychoactive compounds against the receptorome and present two examples (Salvia divinorum, the “magic mint” hallucinogen and Banisteriopsis caapi, the main component of Ayahuasca, a psychoactive beverage) where HTS enabled the identification of the molecular target of each compound.

O’connor, K. A., & Roth, B. L. (2005). Screening the receptorome for plant-based psychoactive compounds. Life sciences, 78(5), 506-511. 10.1016/j.lfs.2005.09.002
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