Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT_2C Receptor and Dual 5-HT_2C/5-HT_2A Receptor Modulators

Abstract

The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

“…LSD and psilocin, the active metabolite of psilocybin, exhibit similar affinity at the 5-HT 2A R and 5-HT 2B R in vitro ( Porter et al, 1999 ), but neither are projected to pose risk for valvulopathy, particularly on acute dosing ( Tagen et al, 2023 ). However, given the critical liability of off-target 5-HT 2B R agonist actions ( Horvath et al, 2004 ; Hutcheson et al, 2011 ), current efforts to identify 5-HT 2A R-selective agonists as novel chemical entities require 5-HT 2B R affinity and efficacy screening early in molecule discovery ( Cao et al, 2022 ; Chen et al, 2023 ; Cunningham et al, 2023 ).…”

“…A positive allosteric modulator ( PAM ) can increase receptor functional responses and/or the intrinsic affinity for the orthosteric ligand through binding to sites on GPCRs that are topographically distinct from the orthosteric site targeted by endogenous (i.e., 5-HT) and synthetic agonists ( Lindsley et al, 2016 ; Wold et al, 2019a ). Several medicinal chemistry campaigns reported 5-HT 2C R PAMs with pharmacological profiles different from agonists ( Garcia-Carceles et al, 2017 ; Wold et al, 2019b ; Singh et al, 2019 ; Wild et al, 2019 ; Wold et al, 2020 ; Chen et al, 2023 ). In this light, oleamide is an intriguing example of an endogenous lipid in mammals ( Arafat et al, 1989 ; Cravatt et al, 1995 ) that controls behavior ( Hedlund et al, 2003 ; Soria-Gomez et al, 2010 ; Prospero-Garcia et al, 2016 ; Mendez-Diaz et al, 2019 ) and activates 5-HT 2A R signaling ( Cao et al, 2022 ), but non-selectively ( Thomas et al, 1997 ; Boger et al, 1998 ; Cheer et al, 1999 ; Hedlund et al, 1999 ; Fedorova et al, 2001 ).…”

“…In this light, oleamide is an intriguing example of an endogenous lipid in mammals ( Arafat et al, 1989 ; Cravatt et al, 1995 ) that controls behavior ( Hedlund et al, 2003 ; Soria-Gomez et al, 2010 ; Prospero-Garcia et al, 2016 ; Mendez-Diaz et al, 2019 ) and activates 5-HT 2A R signaling ( Cao et al, 2022 ), but non-selectively ( Thomas et al, 1997 ; Boger et al, 1998 ; Cheer et al, 1999 ; Hedlund et al, 1999 ; Fedorova et al, 2001 ). A recent synthetic campaign resulted in a series of oleamide-based analogues characterized as selective 5-HT 2C R PAMs or dual 5-HT 2C R/5-HT 2A R PAMs ( Chen et al, 2023 ), as seen with another the natural product derivative PNU-69176E ( Im et al, 2003 ; Ding et al, 2012 ). In the process, CTW0404 and CTW0419 were identified as potential 5-HT 2A R PAMs which exhibit distinct pharmacological profiles relative to 5-HT 2A R agonists (WO2023023287A1) ( Zhou et al, 2023 ).…”

Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists

“…Within this set, the relatively higher potency observed for 6a and 16 align with the available published data for the corresponding tryptamines, in which a 5-MeO or 5-OH substitution in the context of the N , N -dimethylamine motif (5-MeO-DMT and bufotenin, respectively) are among the most potent tryptamines described in the literature. , Because the more potent analogs in the present series do not show appreciable selectivity for 5-HT 2A relative to 5-HT 2B and 5-HT 2C , and in fact are largely 5-HT 2B -preferring, this appreciable 5-HT 2B agonist activity may elicit problematic cardiotoxicities for these and related tryptamines . Historically, there are no examples of orthosteric tryptamines with high selectivity across 5-HT 2 subtypes due to the highly conserved nature of the orthosteric binding pocket, although examples of substituted phenethylamines with higher 5-HT 2A selectivity have been reported. − Recently, additional chemotypes with some degree of 5-HT 2A subtype selectivity have started to emerge in the literature, and an allosteric approach may prove fruitful toward this end. ,, …”

Identification of Spiro[chromene-2,4′-piperidine]s as Potent, Selective, and Gq-Biased 5-HT2C Receptor Partial Agonists

“…To date, many efforts have been made to identify 5-HT 2C R agonists − and positive allosteric modulators. − 5-HT 2C R agonists generally possess a high structural similarity to the endogenous ligand serotonin (5-HT), as depicted in Figure and Figure S1, consisting of a basic amine, an aromatic ring, and a linker connecting them. Only lorcaserin has once been approved by the FDA as a selective 5-HT 2C R agonist for the treatment of obesity; unfortunately, it was later withdrawn from the market due to concerns regarding potential increased risk of cancer associated with long-term use .…”