RO5166017

Last updated
RO5166017
RO5166017 structure.png
Clinical data
Drug class Trace amine-associated receptor 1 (TAAR1) partial or near-full agonist
Identifiers
  • (S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C12H17N3O
Molar mass 219.288 g·mol−1
3D model (JSmol)
  • NC1=N[C@@H](CN(C2=CC=CC=C2)CC)CO1
  • InChI=1S/C12H17N3O/c1-2-15(11-6-4-3-5-7-11)8-10-9-16-12(13)14-10/h3-7,10H,2,8-9H2,1H3,(H2,13,14)/t10-/m0/s1
  • Key:PPONHQQJLWPUPH-JTQLQIEISA-N

RO5166017, or RO-5166017, is a drug developed by Hoffmann-La Roche which acts as a potent and selective agonist for the trace amine-associated receptor 1 (TAAR1), with no significant activity at other targets. [1] [2] [3] It is a partial agonist or near-full agonist depending on the species. [4] [3]

Contents

The drug is important for the study of the TAAR1 receptor, as while numerous other compounds are known which act as TAAR1 agonists, such as methamphetamine, MDMA, and 3-iodothyronamine, all previously known TAAR1 agonists are either weak and rapidly metabolized (endogenous ligands), or have strong pharmacological activity at other targets (amphetamines, thyronamines), making it very difficult to assess which effects are due to TAAR1 activation. The discovery of RO-5166017 allows purely TAAR1 mediated effects to be studied.

Pharmacology

Pharmacodynamics

Actions

RO5166017 is a partial agonist or near-full agonist of the TAAR1 depending on the species examined. [4] [3] Its EC50 Tooltip half-maximal effective concentration values are 3.3 to 8.0 nM for the mouse TAAR1 (mTAAR1), 14 nM for the rat TAAR1 (rTAAR1), 97 nM for the cynomolgus monkey TAAR1, and 55 nM for the human TAAR1. [4] [3] Its Emax Tooltip maximal efficacy values are 65 to 72% for the mTAAR1, 90% for the rTAAR1, 81% for the cynomolgus monkey TAAR1, and 95% for the hTAAR1. [4] [3] RO5166017 is selective for the TAAR1 over a large array of other targets. [3]

RO5166017 at TAAR1 in different species [4] [3]
Species Affinity (Ki, nM) EC50 Tooltip half-maximal effective concentration (nM) Emax Tooltip maximal efficacy (%)
Mouse 1.93.3–8.065–72%
Rat 2.71490%
Monkey 249781%
Human 315595%

Effects

RO5166017 has been found to inhibit the firing rates of ventral tegmental area (VTA) dopaminergic neurons and dorsal raphe nucleus (DRN) serotonergic neurons in mouse brain slices ex vivo . [1] [5] [3] [6] Conversely, it had no effect on the firing rates of locus coeruleus (LC) noradrenergic neurons, an area where TAAR1 is not expressed. [7] [3] The effects of RO5166017 on monoaminergic neuron firing frequencies were absent in TAAR1 knockout mice and could be reversed by the TAAR1 antagonist RTI-7470-44, indicating that they were mediated by TAAR1 activation. [1] [3] [6] Similar effects have been observed with the TAAR1 full agonist p-tyramine. [8] [3] [9] [10] Likewise, RO5166017 inhibited electrically evoked dopamine release in dorsal striatum (DStr) and nucleus accumbens (NAc) mouse brain slices ex vivo. [11] [12] [13] Inhibition of NAc dopamine overflow by RO5166017 could be reversed by the TAAR1 antagonist EPPTB. [12] [13] Neither RO5166017 nor EPPTB had any effect on measures of dopamine reuptake or clearance (tau and half-life) in dopaminergic brain slices ex vivo. [14] [13]

Previous in-vitro studies found that TAAR1 could activate several signaling cascades including PKA, PKC, ERK1/2, and CREB. [15] However, RO5166017 did not affect these signaling pathways, nor GSK3β, in rats in vivo , and instead selectively and TAAR1-dependently inhibited CaMKIIα activity in the NAc. [15]

In animal studies, RO5166017 has little or no effect on locomotor activity itself. [3] [15] In contrast to psychostimulants like amphetamine and cocaine, it does not show stimulant-like or rewarding effects across a broad dose range. [16] The drug dose-dependently suppresses cocaine-induced hyperlocomotion and stereotypies. [1] [5] [14] [8] [3] Likewise, it suppresses hyperlocomotion induced by the NMDA receptor antagonist L-687,414. [1] [3] In dopamine transporter (DAT) knockout mice, which show spontaneous hyperactivity in novel environments, RO5166017 suppresses hyperlocomotion. [14] [8] [3] These effects of RO5166017 are similar to those of antipsychotics like haloperidol and olanzapine. [3] They are absent in TAAR1 knockout mice, indicating that they are mediated by the TAAR1. [5] [3] These findings indicate that RO5166017 has antipsychotic-like effects. [3]

RO5166017 has been found to inhibit expression, though not reconsolidation or retention, of cocaine-induced conditioned place preference (CPP) in mice. [1] [5] [17] Systemic administration or microinjection of RO5166017 into various brain regions has been found to inhibit other cocaine-induced relapse-like behaviors in rodents as well. [1] [18] [15] As with cocaine, RO5166017 has been found to inhibit nicotine-induced dopamine release in the NAc and to reduce nicotine intake and relapse-like behaviors. [1] [5] [19]

RO5166017 has been shown shown to prevent stress-induced hyperthermia in rodents. [3] It has shown robust aversive effects in rodents, similarly to other TAAR1 agonists like RO5256390 and RO5263397. [20] [21] RO5166017 has shown anxiolytic-like effects in mice. [3] It has been found to produce anti-impulsivity-like effects in mice. [5] [22] The drug has been found to augment 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurodegeneration in mice and to counteract levodopa-induced contralateral rotations and dyskinesia. [4] [23] RO5166017 has shown anti-post-traumatic stress disorder (PTSD)-like effects in rodents. [24]

Pharmacokinetics

RO5166017 has shown favorable pharmacokinetic properties for in vivo use. [1] [3]

History

RO5166017 was first described in the scientific literature by 2011. [3] It was the first selective TAAR1 agonist to be discovered. [1] [25]

See also

Related Research Articles

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

<span class="mw-page-title-main">3,4-Methylenedioxyamphetamine</span> Empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family

3,4-Methylenedioxyamphetamine (MDA), sometimes referred to as sass, is an empathogen-entactogen, stimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.

<span class="mw-page-title-main">Phentermine</span> Weight loss medication

Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth.

<span class="mw-page-title-main">3-Iodothyronamine</span> Chemical compound

3-Iodothyronamine (T1AM) is an endogenous thyronamine. It is a high-affinity ligand of the trace amine-associated receptor 1 (TAAR1). T1AM is the most potent endogenous TAAR1 agonist yet discovered. It is also an agonist of the TAAR2 and TAAR5 with similar potency as for the TAAR1 (all in the case of the human proteins). T1AM is not a ligand of the thyroid hormone receptors. However, it is additionally a ligand of various monoamine and other receptors. For instance, it is a muscarinic acetylcholine receptor antagonist.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene.

<span class="mw-page-title-main">3-Methoxytyramine</span> Chemical compound

3-Methoxytyramine (3-MT), also known as 3-methoxy-4-hydroxyphenethylamine, is a human trace amine and the major metabolite of the monoamine neurotransmitter dopamine. It is formed by the introduction of a methyl group to dopamine by the enzyme catechol-O-methyltransferase (COMT). 3-MT can be further metabolized by the enzyme monoamine oxidase (MAO) to form homovanillic acid (HVA), which is then typically excreted in the urine.

<i>para</i>-Chloroamphetamine Chemical compound

para-Chloroamphetamine (PCA), also known as 4-chloroamphetamine (4-CA), is a serotonin–norepinephrine–dopamine releasing agent (SNDRA) and serotonergic neurotoxin of the amphetamine family. It is used in scientific research in the study of the serotonin system, as a serotonin releasing agent (SRA) at lower doses to produce serotonergic effects, and as a serotonergic neurotoxin at higher doses to produce long-lasting depletions of serotonin.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.

<span class="mw-page-title-main">EPPTB</span> Chemical compound

EPPTB, also known as RO5212773 or RO-5212773, is a drug developed by Hoffmann-La Roche which acts as a potent and selective antagonist or inverse agonist of the trace amine-associated receptor 1 (TAAR1). The drug was the first selective antagonist developed for the TAAR1. It is a potent agonist of the mouse and rat TAAR1, but is dramatically less potent as an agonist of the human TAAR1. EPPTB has been used in scientific research to demonstrate an important role for TAAR1 in regulation of dopaminergic signaling in the limbic system.

<i>o</i>-Phenyl-3-iodotyramine Chemical compound

o-Phenyl-3-iodotyramine (o-PIT) is a drug which acts as a selective agonist for the trace amine-associated receptor 1 (TAAR1). It has reasonable selectivity for TAAR1 but relatively low potency, and is rapidly metabolised in vivo, making it less useful for research than newer ligands such as RO5166017. Its EC50Tooltip half-maximal effective concentration values have been reported to be 35 nM for the mouse TAAR1, 2.4 nM at the rat TAAR1, and 9.5 nM at the human TAAR1.

<span class="mw-page-title-main">Locomotor activity</span> Behavioral measure in animals

Locomotor activity is a measure of animal behavior which is employed in scientific research.

<span class="mw-page-title-main">Monoaminergic activity enhancer</span> Class of compounds in the nervous system

Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of drugs that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release. That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse.

<span class="mw-page-title-main">RO5256390</span> Chemical compound

RO5256390 or RO-5256390 is a drug developed by Hoffmann-La Roche which acts as an agonist for the trace amine associated receptor 1 (TAAR1). It is a full agonist of the rat, cynomolgus monkey, and human TAAR1, but a partial agonist of the mouse TAAR1.

<span class="mw-page-title-main">RTI-7470-44</span> Potent human TAAR1 antagonist

RTI-7470-44 is a potent and selective antagonist of the human trace amine-associated receptor 1 (TAAR1) which is used in scientific research. It was discovered in 2022 and is the first potent antagonist of the human TAAR1 to be identified, following the potent mouse TAAR1 inverse agonist EPPTB in 2009.

<span class="mw-page-title-main">RO5263397</span> TAAR1 agonist

RO5263397, or RO-5263397, is a trace amine-associated receptor 1 (TAAR1) partial or full agonist which is used in scientific research. It is the most well-studied of all of the synthetic TAAR1 ligands. In addition to its use in research, RO5263397 is or was under development for potential clinical use as a medication.

<span class="mw-page-title-main">RO5203648</span> Pharmaceutical compound

RO5203648 is a trace amine-associated receptor 1 (TAAR1) partial agonist. It is a potent and highly selective partial agonist of both rodent and primate TAAR1. The drug suppresses the effects of psychostimulants like cocaine and methamphetamine. It also produces a variety of other behavioral effects, such as antidepressant-like, antipsychotic-like, and antiaddictive effects. Research with RO5203648 has led to interest in TAAR1 agonists for potential treatment of drug addiction. RO5203648 itself was not developed for potential medical use due to poor expected human pharmacokinetics.

<span class="mw-page-title-main">RO5073012</span> Pharmaceutical compound

RO5073012 is a selective low-efficacy partial agonist of the trace amine-associated receptor 1 (TAAR1) which has been used in scientific research. TAAR1 partial agonists like RO5073012 can have agonist- or antagonist-like effects at the TAAR1 depending on the context and level of TAAR1 signaling.

<span class="mw-page-title-main">L-687,414</span> Pharmaceutical compound

L-687,414 is a glycine-site NMDA receptor antagonist or low-efficacy partial agonist which is used in scientific research. It a close analogue of HA-966. The drug has been found to produce hyperlocomotion, analgesia or antinociceptive effects, anticonvulsant effects, and neuroprotective effects in animals. In contrast to uncompetitive NMDA receptor antagonists like ketamine and phencyclidine (PCP), L-687,414 has not been associated with the development of brain vacuoles in animals.

References

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  2. ↑ Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, Metzler V, Chaboz S, Groebke Zbinden K, Galley G, Norcross RD, Tuerck D, Bruns A, Morairty SR, Kilduff TS, Wallace TL, Risterucci C, Wettstein JG, Hoener MC (May 2013). "A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight". Mol Psychiatry. 18 (5): 543–556. doi:10.1038/mp.2012.57. PMID   22641180.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc Natl Acad Sci U S A. 108 (20): 8485–8490. Bibcode:2011PNAS..108.8485R. doi: 10.1073/pnas.1103029108 . PMC   3101002 . PMID   21525407.
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  7. ↑ Dedic N, Dworak H, Zeni C, Rutigliano G, Howes OD (December 2021). "Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies". Int J Mol Sci. 22 (24): 13185. doi: 10.3390/ijms222413185 . PMC   8704992 . PMID   34947997.
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  9. ↑ Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC (March 2008). "Trace amine-associated receptor 1 modulates dopaminergic activity". J Pharmacol Exp Ther. 324 (3): 948–956. doi:10.1124/jpet.107.132647. PMID   18083911.
  10. ↑ Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC, Bettler B (November 2009). "The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system". Proc Natl Acad Sci U S A. 106 (47): 20081–6. Bibcode:2009PNAS..10620081B. doi: 10.1073/pnas.0906522106 . PMC   2785295 . PMID   19892733.
  11. ↑ Pei Y, Asif-Malik A, Canales JJ (2016). "Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications". Front Neurosci. 10: 148. doi: 10.3389/fnins.2016.00148 . PMC   4820462 . PMID   27092049.
  12. 1 2 Rutigliano G, Accorroni A, Zucchi R (2017). "The Case for TAAR1 as a Modulator of Central Nervous System Function". Front Pharmacol. 8: 987. doi: 10.3389/fphar.2017.00987 . PMC   5767590 . PMID   29375386.
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  14. 1 2 3 Liu JF, Li JX (2018). "TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg". Front Pharmacol. 9: 279. doi: 10.3389/fphar.2018.00279 . PMC   5881156 . PMID   29636691.
  15. 1 2 3 4 Liu J, Wu R, Seaman R, Manz KM, Johnson B, Vu J, Huang Y, Zhang Y, Robison AJ, Neve R, Grueter BA, Dietz D, Li JX (April 2022). "TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc". Mol Psychiatry. 27 (4): 2136–2145. doi:10.1038/s41380-022-01448-3. PMC   9829124 . PMID   35079125. Previous in vitro studies showed that TAAR1 activation stimulated several signaling cascades, including PKA, PKC, ERK1/2, and CREB [13, 38]. For example, a recent study showed that intracellular TAAR1 mediated the effects of amphetamine, a TAAR1 agonist, on RhoA and PKA signaling through G13 and to GS α-subunits on the midbrain slice of mice [39]. However, our present study showed that the TAAR1 agonist RO5166017 did not affect the activities of PKA, PKC, ERK1/2, CREB, or GSK3β, but selectively inhibited CaMKIIα in the NAc of rats. The discrepancies could be due to differences between in vitro and in vivo microenvironments. We also found that RO5166017 did not affect CaMKIIα activity in TAAR1-KO rats, indicating that the inhibitory effects of TAAR1 activation on CaMKIIα were specific.
  16. ↑ Revel FG, Hoener MC, Renau-Piqueras J, Canales JJ (2012). "Targeting Trace-Amine Associated Receptors in the Treatment of Drug Addiction". In Canales JJ (ed.). Emerging Targets for Drug Addiction Treatment. Nova Science Publishers. pp. 203–216. RO5166017 lacks stimulant effects when given alone within an ample dose range (0.3-20 mg/kg). In the CPP procedure, RO5166017 did not exhibit rewarding properties within the same dose range, but failed to alter cocaine (15 mg/kg)-induced CPP (unpublished observations). These data suggest that RO5166017 does not show stimulant-like properties, displaying the capacity to prevent the hyperactivity, but not the rewarding-like effects of cocaine in the CPP paradigm.
  17. ↑ Liu JF, Thorn DA, Zhang Y, Li JX (July 2016). "Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory". Int J Neuropsychopharmacol. 19 (7): pyw009. doi:10.1093/ijnp/pyw009. PMC   4966273 . PMID   26822713.
  18. ↑ Liu JF, Siemian JN, Seaman R, Zhang Y, Li JX (January 2017). "Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior". J Neurosci. 37 (4): 882–892. doi:10.1523/JNEUROSCI.2006-16.2016. PMC   5296782 . PMID   28123023.
  19. ↑ Liu JF, Seaman R, Siemian JN, Bhimani R, Johnson B, Zhang Y, Zhu Q, Hoener MC, Park J, Dietz DM, Li JX (November 2018). "Role of trace amine-associated receptor 1 in nicotine's behavioral and neurochemical effects". Neuropsychopharmacology. 43 (12): 2435–2444. doi:10.1038/s41386-018-0017-9. PMC   6180004 . PMID   29472642.
  20. ↑ Shabani S, Houlton S, Ghimire B, Tonello D, Reed C, Baba H, Aldrich S, Phillips TJ (September 2023). "Robust aversive effects of trace amine-associated receptor 1 activation in mice". Neuropsychopharmacology. 48 (10): 1446–1454. doi:10.1038/s41386-023-01578-4. PMC   10425385 . PMID   37055488.
  21. ↑ Liu J, Wu R, Johnson B, Zhang Y, Zhu Q, Li JX (October 2022). "Selective TAAR1 agonists induce conditioned taste aversion". Psychopharmacology (Berl). 239 (10): 3345–3353. doi:10.1007/s00213-022-06222-5. PMID   36056214.
  22. ↑ Espinoza S, Lignani G, Caffino L, Maggi S, Sukhanov I, Leo D, Mus L, Emanuele M, Ronzitti G, Harmeier A, Medrihan L, Sotnikova TD, Chieregatti E, Hoener MC, Benfenati F, Tucci V, Fumagalli F, Gainetdinov RR (August 2015). "TAAR1 Modulates Cortical Glutamate NMDA Receptor Function". Neuropsychopharmacology. 40 (9): 2217–2227. doi:10.1038/npp.2015.65. PMC   4613611 . PMID   25749299.
  23. ↑ Alvarsson A, Zhang X, Stan TL, Schintu N, Kadkhodaei B, Millan MJ, Perlmann T, Svenningsson P (October 2015). "Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission". J Neurosci. 35 (41): 14057–14069. doi:10.1523/JNEUROSCI.1312-15.2015. PMC   6608178 . PMID   26468205.
  24. ↑ Peng L, Zhang J, Feng J, Ge J, Zou Y, Chen Y, Xu L, Zeng Y, Li JX, Liu J (October 2024). "Activation of trace amine-associated receptor 1 ameliorates PTSD-like symptoms". Biochem Pharmacol. 228: 116236. doi:10.1016/j.bcp.2024.116236. PMID   38670437.
  25. ↑ Cichero E, Espinoza S, Gainetdinov RR, Brasili L, Fossa P (April 2013). "Insights into the structure and pharmacology of the human trace amine-associated receptor 1 (hTAAR1): homology modelling and docking studies". Chem Biol Drug Des. 81 (4): 509–516. doi:10.1111/cbdd.12018. PMID   22883051.
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