Further insights into the pharmacology of the human trace amine-associated receptors: discovery of novel ligands for TAAR1 by a virtual screening approach.

Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor that is expressed in brain and periphery and responds to a class of compounds called trace amines, such as ß-phenylethylamine (ß-PEA), tyramine, tryptamine, octopamine. The receptor is known to have a very rich pharmacology and could be also activated by different classes of compounds, including dopaminergic, adrenergic and serotonergic ligands. It is expected that targeting hTAAR1 could provide a novel pharmacological approach for several human disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder, Parkinson's disease and metabolic diseases. Only recently, a small number of selective hTAAR1 agonists (among which RO5166017 and T1 AM) and antagonist (EPPTB), have been reported in literature. With the aim to identify new molecular entities able to act as ligands for this target, we used an homology model for the hTAAR1 and performed a virtual screening procedure on an in-house database of compounds. A number of interesting molecules were selected and by testing them in an in vitro assay we found several agonists and one antagonist, with activities in the low micromolar range. These compounds could represent the starting point for the development of more potent and selective TAAR1 ligands.

Synthesis and structure-activity relationships of 1-aralkyl-4-benzylpiperidine and 1-aralkyl-4-benzylpiperazine derivatives as potent sigma ligands.

In the attempt to define more accurately structure-affinity relationships for sigma(1) and sigma(2) ligands, we synthesized and tested on sigma subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine, in which the effect of modifications on the aralkyl moiety was studied in a systematic way. The affinity of the compounds here described varied to a great extent, with a sigma(2)/sigma(1) selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative to bind to sigma(1) receptors in a different way than piperidines, we synthesized and tested a series of piperazine compounds; the comparison of their affinity with that of the corresponding piperidines strongly supports the possibility of a different binding mode. While the compounds here described are on the whole selective for sigma vs serotonin 5-HT(1A) and dopamine D(2) receptors, 9aa, 9ba and 9ab possess a remarkable affinity for both sigma and 5-HT(1A) receptors, with K(i) in the nanomolar range, and are selective with respect to D(2) receptors. They displayed also a partial agonist profile in a human 5-HT(1A) [(35)S]GTP gamma S binding assay, suggesting their potential use as atypical antipsychotic agents.