nuke
Bluelighter
- Joined
- Nov 7, 2004
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- 4,191
I'm curious now because of this study:
Sounds like a new target for stimulant drugs, and also perhaps antipsychotics.
http://jpet.aspetjournals.org/cgi/content/abstract/321/1/178Trace Amine-Associated Receptor 1 Displays Species-Dependent Stereoselectivity for Isomers of Methamphetamine, Amphetamine, and Para-Hydroxyamphetamine
E. A. Reese, J. R. Bunzow, S. Arttamangkul, M. S. Sonders, and D. K. Grandy
Department of Physiology and Pharmacology (E.A.R., J.R.B., D.K.G.) and Vollum Institute (S.A.), Oregon Health & Science University, Portland, Oregon; and Center for Molecular Recognition, Columbia University, New York, New York (M.S.S.)
The synthetic amines methamphetamine (METH), amphetamine (AMPH), and their metabolite para-hydroxyamphetamine (POHA) are chemically and structurally related to the catecholamine neurotransmitters and a small group of endogenous biogenic amines collectively referred to as the trace amines (TAs). Recently, it was reported that METH, AMPH, POHA, and the TAs para-tyramine (TYR) and -phenylethylamine (PEA) stimulate cAMP production in human embryonic kidney (HEK)-293 cells expressing rat trace amine-associated receptor 1 (rTAAR1). The discovery that METH and AMPH activate the rTAAR1 motivated us to study the effect of these drugs on the mouse TAAR1 (mTAAR1) and a human-rat chimera (hrChTAAR1). Furthermore, because S-(+)-isomers of METH and AMPH are reported to be more potent and efficacious in vivo than R-(–), we determined the enantiomeric selectivity of all three species of TAAR1. In response to METH, AMPH, or POHA exposure, the accumulation of cAMP by HEK-293 cells stably expressing different species of TAAR1 was concentration- and isomer-dependent. EC50 values for S-(+)-METH were 0.89, 0.92, and 4.44 µM for rTAAR1, mTAAR1, and h-rChTAAR1, respectively. PEA was a potent and full agonist at each species of TAAR1, whereas TYR was a full agonist for the rodent TAAR1s but was a partial agonist at h-rChTAAR1. Interestingly, both isomers of METH were full agonists at mTAAR1 and h-rChTAAR1, whereas both were partial agonists at rTAAR1. Taken together, these in vitro results suggest that, in vivo, TAAR1 could be a novel mediator of the effects of these drugs.
http://www.ncbi.nlm.nih.gov/pubmed/18420141Toward deciphering the code to aminergic G protein-coupled receptor drug design.
Tan ES, Groban ES, Jacobson MP, Scanlan TS.
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
The trace amine-associated receptor 1 (TAAR(1)) is a biogenic amine G protein-coupled receptor (GPCR) that is potently activated by 3-iodothyronamine (1, T(1)AM) in vitro. Compound 1 is an endogenous derivative of the thyroid hormone thyroxine which rapidly induces hypothermia, anergia, and bradycardia when administered to mice. To explore the role of TAAR(1) in mediating the effects of 1, we rationally designed and synthesized rat TAAR(1) superagonists and lead antagonists using the rotamer toggle switch model of aminergic GPCR activation. The functional activity of a ligand is proposed to be correlated to its probable interactions with the rotamer switch residues; agonists allow the rotamer switch residues to toggle to their active conformation, whereas antagonists interfere with this conformational transition. These agonist and antagonist design principles provide a conceptual model for understanding the relationship between the molecular structure of a drug and its pharmacological properties.
http://www.ncbi.nlm.nih.gov/pubmed/18083911Trace amine-associated receptor 1 modulates dopaminergic activity.
Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC.
Pharmaceuticals Division, Central Nervous System Research, Department PRDNP5 CH, Bldg. 70/331, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
The recent identification of the trace amine-associated receptor (TAAR)1 provides an opportunity to dissociate the effects of trace amines on the dopamine transporter from receptor-mediated effects. To separate both effects on a physiological level, a Taar1 knockout mouse line was generated. Taar1 knockout mice display increased sensitivity to amphetamine as revealed by enhanced amphetamine-triggered increases in locomotor activity and augmented striatal release of dopamine compared with wild-type animals. Under baseline conditions, locomotion and extracellular striatal dopamine levels were similar between Taar1 knockout and wild-type mice. Electrophysiological recordings revealed an elevated spontaneous firing rate of dopaminergic neurons in the ventral tegmental area of Taar1 knock-out mice. The endogenous TAAR1 agonist p-tyramine specifically decreased the spike frequency of these neurons in wild-type but not in Taar1 knockout mice, consistent with the prominent expression of Taar1 in the ventral tegmental area. Taken together, the data reveal TAAR1 as regulator of dopaminergic neurotransmission.
http://www.ncbi.nlm.nih.gov/pubmed/17088868Trace amine-associated receptors and their ligands.
Zucchi R, Chiellini G, Scanlan TS, Grandy DK.
Dipartimento di Scienze dell'Uomo e dell'Ambiente, University of Pisa, Pisa, Italy. [email protected]
Classical biogenic amines (adrenaline, noradrenaline, dopamine, serotonin and histamine) interact with specific families of G protein-coupled receptors (GPCRs). The term 'trace amines' is used when referring to p-tyramine, beta-phenylethylamine, tryptamine and octopamine, compounds that are present in mammalian tissues at very low (nanomolar) concentrations. The pharmacological effects of trace amines are usually attributed to their interference with the aminergic pathways, but in 2001 a new gene was identified, that codes for a GPCR responding to p-tyramine and beta-phenylethylamine but not to classical biogenic amines. Several closely related genes were subsequently identified and designated as the trace amine-associated receptors (TAARs). Pharmacological investigations in vitro show that many TAAR subtypes may not respond to p-tyramine, beta-phenylethylamine, tryptamine or octopamine, suggesting the existence of additional endogenous ligands. A novel endogenous thyroid hormone derivative, 3-iodothyronamine, has been found to interact with TAAR1 and possibly other TAAR subtypes. In vivo, micromolar concentrations of 3-iodothyronamine determine functional effects which are opposite to those produced on a longer time scale by thyroid hormones, including reduction in body temperature and decrease in cardiac contractility. Expression of all TAAR subtypes except TAAR1 has been reported in mouse olfactory epithelium, and several volatile amines were shown to interact with specific TAAR subtypes. In addition, there is evidence that TAAR1 is targeted by amphetamines and other psychotropic agents, while genetic linkage studies show a significant association between the TAAR gene family locus and susceptibility to schizophrenia or bipolar affective disorder.
Sounds like a new target for stimulant drugs, and also perhaps antipsychotics.