From the Promiscuous Asenapine to Potent Fluorescent Ligands Acting at a Series of Aminergic G‑Protein-Coupled Receptors

Monoamine neurotransmitters such
as serotonin, dopamine, histamine, and noradrenaline have important
and varied physiological functions and similar chemical structures.
Representing important pharmaceutical drug targets, the corresponding
G-protein-coupled receptors (termed aminergic GPCRs) belong to the
class of cell membrane receptors and share many levels of similarity
as well. Given their pharmacological and structural closeness, one
could hypothesize the possibility to derivatize a ubiquitous ligand
to afford rapidly fluorescent probes for a large set of GPCRs to be
used for instance in FRET-based binding assays. Here we report fluorescent
derivatives of the nonselective agent asenapine which were designed,
synthesized, and evaluated as ligands of 34 serotonin, dopamine, histamine,
melatonin, acetylcholine, and adrenergic receptors. It appears that
this strategy led rapidly to the discovery and development of nanomolar
affinity fluorescent probes for 14 aminergic GPCRs. Selected probes
were tested in competition binding assays with unlabeled competitors
in order to demonstrate their suitability for drug discovery purposes.