2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery

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

“…Diethylamine 6c and 5-chloroindazole 14 displayed no appreciable 5-HT 2A functional activity up to 10 μM, whereas 5-hydroxy analog 16 displayed similar potency to 6a for 5-HT 2A (with higher potency for the other subtypes). 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. ,, …”

“…A functional agonist profile at 5-HT 2B , however, does not necessarily guarantee cardiotoxicity, and in fact partial agonists for this receptor have been shown to prevent and treat Sugen-hypoxia-induced PAH in mice . Furthermore, signaling bias may play a role in determining the cardiotoxic potential of a given compound; compounds including ropinirole and BW723C86 are not known to induce cardiotoxicity despite being potent functional agonists in the Ca 2+ calcium flux assay. , Further characterization of the present compounds will be needed in order to fully understand any associated risks …”

“…In our hands, 19a and 19f appear to be strongly 5-HT 2B -preferring relative to 5-HT 2A , indicating that the selectivity for 5-HT 2A in the context of the tetrahydropyridine series may prove challenging. As with the acyclic analogs described in Table , this potent 5-HT 2B agonist activity is concerning with respect to the potential to induce pulmonary arterial hypertension (PAH), valvular heart disease (VHD), and related cardiopathies . A functional agonist profile at 5-HT 2B , however, does not necessarily guarantee cardiotoxicity, and in fact partial agonists for this receptor have been shown to prevent and treat Sugen-hypoxia-induced PAH in mice .…”

“… 30 , 31 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. 32 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. 33 − 35 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.…”

“…20 This large discrepancy between reports for the 5-HT 2B subtype selectivity profile for this compound is noteworthy (483 nM in our hands vs >10 μM), given that agonist activity (nor-dexfenfluramine and related clinical 5-HT 2B agonists) at this receptor presents a well-validated risk for cardiotoxicity. 32 Although it is possible that differences in cell line background and/or receptor expression levels may partially account for this disparate selectivity data (see Supporting Information ), this finding highlights the need for rigorous characterization of 5-HT 2A agonists (both known and novel) across multiple cell backgrounds and functional readouts if such compounds are to be safely profiled in the clinic.…”