Modulating the Serotonin Receptor Spectrum of Pulicatin Natural Products

Abstract

Serotonin (5-HT) receptors are important in health and disease, but the existence of 14 subtypes necessitates selective ligands. Previously, the pulicatins were identified as ligands that specifically bound to the subtype 5-HT2B in the 500 nM-10 μM range and that exhibited in vitro effects on cultured mouse neurons. Here, we examined the structure-activity relationship (SAR) of 30 synthetic and natural pulicatin derivatives using binding, receptor functionality, and in vivo assays. The results reveal the 2-aryl-thiazoline scaffold as a tunable serotonin receptor-targeting pharmacophore. Tests in mice show potential antiseizure and antinociceptive activities at high doses without motor impairment.

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

“… Additional reports of selective 5-HT 2B antagonists with more detailed PK profiles have slowly started to emerge in the literature. , More recently, members of the 2-thiazoline pulicatin class of natural products (and synthetic derivatives) were reported to have high selectivity for 5-HT 2B relative to a broader panel of serotonin receptor subtypes (Figure ). As before, drug-development-enabling PK information is not reported. In 2023, Schieferdecker and Vock reported detailed 5-HT 2B pharmacophore models which are likely to aid in the development of next-generation ligands with robust subtype selectivity …”

Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration

“…The only suggested target for aerugine is the 5HT 2B receptor, from which it displaced radioactive lysergic acid diethylamide at low μM concentrations. However, functional data are not available to our knowledge ( Lin et al, 2017 ).…”

Nicotinic Acetylcholine Receptor Partial Antagonist Polyamides from Tunicates and Their Predatory Sea Slugs

“…Our previous work with DRG neurons led to the identification of several families of active marine natural products that we have investigated for antinociceptive efficacy. − In the course of this work, we identified several hits that seemed to target only a small subset of cells, but we had no framework to identify those cells, leading us to develop constellation pharmacology. Here, we show the power of constellation pharmacology to rapidly identify cell-type selective agents with therapeutic promise.…”