A rat G protein-coupled receptor (rTAR1) stimulates cAMP production when exposed to trace amines such as p-tyramine, beta-phenethylamine, tryptamine, and octopamine. Psychostimulant and hallucinogenic amphetamines, ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of catecholamine neurotransmitters also act as potent agonists at this receptor. These findings indicate that trace amines and catecholamine metabolites may be endogenous ligands for a novel intercellular signaling system in the vertebrate brain and periphery. The potency of amphetamines, including MDMA (ecstasy), as rTAR1 agonists suggests that some effects of these drugs may be mediated through this receptor in addition to neurotransmitter transporter proteins.
Ibogaine and its main metabolite noribogaine inhibit the vesicular monoamine transporter 2 (VMAT2) with submicromolar potency, as shown in cell-based assays and two-photon microscopy of mouse brain synaptic vesicle clusters. Noribogaine also induces partial serotonin release from synaptic vesicles and binds VMAT2 at a distinct site from the established inhibitor dihydrotetrabenazine. These compounds additionally inhibit plasma membrane monoamine transporters, prominently the serotonin transporter (SERT), and a novel target, organic cation transporter 2 (OCT2). Several iboga analogs display dual inhibition of VMAT2 and SERT with comparable potencies, termed "Synaptic Reuptake Inhibitors" (SynRIs). This profile explains why ibogaine and noribogaine do not induce catalepsy, unlike other VMAT2 inhibitors, and illustrates the complex "matrix pharmacology" of iboga compounds.