Background: N-2-methoxybenzyl-phenethylamines (NBOMe drugs) are newly used

The in vitro binding of a new subtype‐selective NMDA receptor antagonist, [3H]Ro 25‐6981, to rat brain membranes and sections was characterized. The compound bound to a single site on the membranes with a KD of 3 nM and a Bmax of 1.6 pmol/mg of protein. Specific binding, defined with a new NR2B‐specific antagonist, Ro 04‐5595 [1‐(4‐chlorophenyl)‐2‐methyl‐6‐methoxy‐7‐hydroxy‐1,2,3,4‐tetrahydroisoquinoline], at 10 µM, was fully inhibited by several compounds with the following rank order of affinities—Ro 25‐6981 > CP‐101,606 > Ro 04‐5595 = ifenprodil ≫ eliprodil > haloperidol > spermine > spermidine > MgCl2 > CaCl2—and partially inhibited by competitive glutamate recognition site antagonists. A high density of binding sites was detected, radioautographically, in several layers of the cerebral cortex, in the hippocampus, dentate gyrus, tuberculum olfactorium, caudate putamen, medium densities in the globus pallidus, thalamus, spinal cord dorsal horn, and motoneurons, whereas the cerebellum, pons, and medulla were, with a few exceptions, e.g., locus coeruleus, poorly labeled. Overall, the distribution of [3H]Ro 25‐6981 binding sites correlated well with that of NR2B (but not NR2A) transcripts, revealed by in situ hybridization histochemistry. The high affinity of [3H]Ro 25‐6981 for NR2B‐containing receptors renders this compound the ligand of choice to study the regulation of NR2B‐containing receptor expression.

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Trace amine-associated receptor 1 (TAAR1) has been implicated in the behavioral effects of amphetamine-type stimulant drugs in rodents. TAAR1 has also been suggested as a target for novel medications to treat psychostimulant addiction. We previously reported that binding affinities at TAAR1 can differ between structural analogs of psychostimulants, and species differences have been observed. In this study, we complement our previous findings with additional substances and the determination of functional activation potencies. In summary, we present here pharmacological in vitro profiles of 101 psychoactive substances at human, rat, and mouse TAAR1. p-Tyramine, b-phenylethylamine, and tryptamine were included as endogenous comparator compounds. Functional cAMP measurements and radioligand displacement assays were conducted with human embryonic kidney 293 cells that expressed human, rat, or mouse TAAR1.Most amphetamines, phenethylamine, and aminoindanes exhibited potentially physiologically relevant rat and mouse TAAR1 activation (EC 50 , 5 mM) and showed full or partial (E max , 80%) agonist properties. Cathinone derivatives, including mephedrone and methylenedioxypyrovalerone, exhibited weak (EC 50 5 5-10 mM) to negligible (EC 50 . 10 mM) binding properties at TAAR1. Pipradrols, including methylphenidate, exhibited no affinity for TAAR1. We found considerable species differences in activity at TAAR1 among the highly active ligands, with a rank order of rat . mouse . human. This characterization provides information about the pharmacological profile of psychoactive substances. The species differences emphasize the relevance of clinical studies to translationally complement rodent studies on the role of TAAR1 activity for psychoactive substances.