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PRC200
Systematic (IUPAC) name
(1S,2S)-3-(methylamino)-2-naphthalen-2-yl-1-phenylpropan-1-ol
Identifiers
CAS number  ?
ATC code  ?
PubChem 20631904
Chemical data
Formula C 20H21NO 
Mol. mass 291.386 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

PRC200-SS is an arylalkanolamine TRI being developed by the Mayo Clinic.[1][2] Sympathomimetic PRC200-SS is the PRC050 eutomer,[3] whereas PRC201 is the distomer. These compounds are preceeded by venlafaxine, which Wyeth claims is the first SNRI.[4] Venlafaxine was originaly developed as an "opioid" although original screening returned negative results. Not satisfied with this, the authors continued with venlafaxine and discovered that it exerts its biological actions via interaction with the monoamine receptors.

Silicon containing analog of venlafaxine was prepared and demonstrated to be an active SNRI.

Contents

Chirality

For venlafaxine there is only one chiral centre, although for the PRC compounds, there is a diastereoisomeric pair of racemers to consider.

The exact choice of conditions (e.g. temperature and choice of solvent, etc) can be altered to try and increase the dia/stereo-selectivity.

PRC050 is racemic SS/RR, PRC025 is racemic SR/RS,[3] venlafaxine is racemic;

PRC050 was further resolved into its constituent enantiomers, PRC200 (SS) and PRC201 (RR), respectively.[2]

PRCtwohundred.png
Compound hNET Kd (Ki) hSERT Kd (Ki) hDAT Kd (Ki)
Venlafaxine 1060 (210) 9.0 (39) 9,300 (5,300)
PRC025 19 (10) 6.0 (6.0) 100 (53)
PRC050 0.40 (1.2) 6.0 (12) 120 (43)
PRC200-SS 0.63 (1.5) 2.3 (2.1) 18 (61)
PRC201 42 (?) 210 (?) 200 (?)

As can be seen in the above table, a high eudysmic ratio exists for PRC050 with activity residing in the SS enantiomer (PRC200).

Type of Amine

In contrast to venlafaxine and PRC025, PRC050 is a secondary amine (and not a tertiary amine).

This is like comparing imipramine with desipramine, or amitriptyline with nortriptyline.

N-demethylation has the effect of boosting noradrenergic activity, but does not increase binding to the dopamine active transporter.

Transporter Selectivity

PRC025 has the in vitro MAT order of potency S>N>D whereas for PRC050 the affinity for the transporters is N>S>D.

Currently the thinking is that PRC050 should be preferred to PRC025 on the basis that it is the more potent of the two compounds.

Liang and Richelson actually believe that a nomifensine type analog with an order of potency N>D>S would be optimal.

Their reasoning for N>D is that this would limit abuse liability, and D>S is that this would lessen the risk of serotonin syndrome.

Behavioral Studies on Rodent

Only PRC200 was considered further in behavioral studies.[2]

PRC200-SS is active in the FST and the TST at a dose of 5mg/kg, results are similar to imipramine.

However, PRC200-SS is much more potent than imipramine: 1mg/kg of PRC200-SS is ≈ equivalent to 15mg/kg imipramine.

Importantly, PRC200-SS does not cause LMA and is not self-administered by the rodents, meaning it is unlikely to be reinforcing.

Increasing the dose to 10mg/kg does not enhance the activity of PRC200-SS further, indicating that 5mg/kg is the opimal dosage.

Microdialysis

Concentrations of NE, 5-HT, DA, DOPAC, HVA, and 5-HIAA, were measured in the mPFC and NAc, respectively.[2]

At 10mg/kg NE concentrations were increased by c.f. ~700% respectively in the mPFC.

This is in contrast to the core of the NAc where concentrations of NE were not elevated at all.

The authors rationalized that this is because all the NET dense fibres/tissue lies in the NAc shell and not in the core (?)

In the mPFC concentrations of DA were not elevated at all. Authors claim that this is because of the low density of DAT tissue in the mPFC.

However, in the core of the NAc, DA concentrations were elevated by c.f. ~160% upon administration of 10mg/kg of PRC200-SS.

This is consistent with the drop in cytoplasmic concentrations of HVA and DOPAC that were also measured in this brain region at this dose.

An elevation in the concentration of 5-HT and reduction in the concentration of 5-HIAA were measured, particularly in the mPFC;

however the % change from baseline was less than expected on the basis of the in vitro measurements that were recorded.

Authors resorted to the theory that is known about 5-HT1A (and related) autoreceptors to try and help account for this observation.

SAR

In the initial assessment of these compounds, analogs displaying an increased role at the DAT relative to the other 2 transporters was sought.

R Ar N SERT 5HT NET NE DAT DA
Ph Ph H2 3,050 2,730 12,500 5,780 24K 6,600
c-C6H11 p-anisoyl H2 76 164 1,540 330 4,310 1,460
mesityl Ph H2 118 643 22,500 8,600 340 5,310
t-Bu Ph H2 1,100 14K 47,900 3,800 7,260 4,570
t-Bu 2-naph H2 6.1 14 55 44 27K 120
Ph 2-naph H2 6.2 27 21 7.7 140 6.2
Ph Ph Me2 48 210 2,250 990 12,000 1,550
c-C6H11 p-anisoyl Me2 30 30 1,800 220 3,500 640
mesityl Ph Me2 8.5 57 35,800 8,500 42K 4,880
t-Bu Ph Me2 40 60 3,430 830 21,400 1,200
t-Bu 2-naph Me2 1.2 2.6 29.9 10 340 60
Ph 2-naph Me2 5.59 4.1 44 15 70 12

Syntheses

Nitrile-aldol conditions ensures desired anti-addition product.[5][6][7] PCarlier.png

Vu, A.; Cohn, S.; Terefenko, E.; Moore, W.; Zhang, P.; Mahaney, P.; Trybulski, E.; Goljer, I. et al. (2009). "3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors". Bioorganic & medicinal chemistry letters 19 (9): 2464–2467. doi:10.1016/j.bmcl.2009.03.054. PMID 19329313.   edit Mahaney, P.; Gavrin, L.; Trybulski, E.; Stack, G.; Vu, T.; Cohn, S.; Ye, F.; Belardi, J. et al. (2008). "Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors". Journal of medicinal chemistry 51 (13): 4038–4049. doi:10.1021/jm8002262. PMID 18557608.   edit

Wyeth.png

Patents

U.S. Patent 6,069,177 U.S. Patent 6,700,018 U.S. Patent 6,914,080

U.S. Patent Application 11/529,441 

References

  1. ^ Y. Liang, E. Richelson. Triple Reuptake Inhibitors: Next-Generation Antidepressants. Primary Psychiatry. 2008;15(4):50-56.
  2. ^ a b c d Liang, Y.; Shaw, A.; Boules, M.; Briody, S.; Robinson, J.; Oliveros, A.; Blazar, E.; Williams, K. et al. (2008). "Antidepressant-like pharmacological profile of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS)". The Journal of pharmacology and experimental therapeutics 327 (2): 573–583. doi:10.1124/jpet.108.143610. PMID 18689611.   edit
  3. ^ a b Shaw, A.; Boules, M.; Zhang, Y.; Williams, K.; Robinson, J.; Carlier, P.; Richelson, E. (2007). "Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050". European journal of pharmacology 555 (1): 30–36. doi:10.1016/j.ejphar.2006.10.004. PMID 17109850.   edit
  4. ^ Carlier, PR; Lo; Lo; Richelson; Tatsumi; Reynolds; Sharma (1998). "Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group". Bioorganic & medicinal chemistry letters 8 (5): 487–92. doi:10.1016/S0960-894X(98)00062-6. PMID 9871604.   edit
  5. ^ Carlier, P. R.; Lo, K. M.; Lo, M. M. C.; Williams, I. D. (1995). "Anti-Selective Aldol Reaction of Benzylic Nitriles and Synthesis of .gamma.-Amino Alcohols". The Journal of Organic Chemistry 60: 7511. doi:10.1021/jo00128a025.   edit
  6. ^ Carlier, P. R.; Lo, K. M. (1994). "2,3-Anti Selective Aldol Reaction of Phenylacetonitrile". The Journal of Organic Chemistry 59: 4053. doi:10.1021/jo00094a011.   edit
  7. ^ Carlier, P. R.; Lo, K. M.; Lo, M. M. -C.; Lo, P. C. -K.; Lo, C. W. -S. (1997). "Synthetic Optimization and Structural Limitations of the Nitrile Aldol Reaction". The Journal of Organic Chemistry 62: 6316. doi:10.1021/jo9702148.   edit
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