PRC200-SS: Difference between revisions

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{{Short description|Triple reuptake inhibitor investigated by the Mayo Clinic}}

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 429978263

| Watchedfields = changed

| IUPAC_name = (1S,2S)-3-(methylamino)-2-naphthalen-2-yl-1-phenylpropan-1-ol

| verifiedrevid = 451223794

| IUPAC_name = (1''S'',2''S'')-3-(Methylamino)-2-naphthalen-2-yl-1-phenylpropan-1-ol

| image = PRC200 structure.png

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| pregnancy_category =

| legal_status =

| routes_of_administration =

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| metabolism =

| elimination_half-life =

| excretion =

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number =

| CAS_number = 492434-58-9

| ATC_prefix =

| ATC_suffix =

| ATC_supplemental =

| PubChem = 20631904

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 19318181

| C=20 | H=21 | N=1 | O=1

| smiles = O[C@H](c1ccccc1)[C@H](CNC)c2cc3ccccc3cc2

| molecular_weight = 291.386 g/mol

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| smiles = CNC[C@H](C1=CC2=CC=CC=C2C=C1)[C@@H](C3=CC=CC=C3)O

| StdInChI = 1S/C20H21NO/c1-21-14-19(20(22)16-8-3-2-4-9-16)18-12-11-15-7-5-6-10-17(15)13-18/h2-13,19-22H,14H2,1H3/t19-,20-/m1/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = RSZGIFQDUIROGN-WOJBJXKFSA-N

}}

'''PRC200-SS''' is an experimental drug of the [[triple reuptake inhibitor]] class that was investigated by the [[Mayo Clinic]].<ref name=Liang>{{cite journal | vauthors = Liang Y, Shaw AM, Boules M, Briody S, Robinson J, Oliveros A, Blazar E, Williams K, Zhang Y, Carlier PR, Richelson E | display-authors = 6 | title = Antidepressant-like pharmacological profile of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS) | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 2 | pages = 573–83 | date = November 2008 | pmid = 18689611 | doi = 10.1124/jpet.108.143610 | s2cid = 12635418 }}</ref><ref>{{Cite web | url = http://technologies.ventures.mayoclinic.org/technologies/2011-044_triple-reuptake-inhibitors-for-the-treatment-of-depression | title = Triple Reuptake Inhibitors for the Treatment of Depression | publisher = Mayo Clinic Ventures }}</ref>

'''PRC200-SS''' is an [[arylalkanolamine]] TRI being developed by the [[Mayo Clinic]].<ref>Y. Liang, E. Richelson. Triple Reuptake Inhibitors: Next-Generation Antidepressants. [http://mbldownloads.com/0408PP_Liang_CME.pdf Primary Psychiatry. 2008;15(4):50-56.]</ref><ref name=Liang>{{Cite pmid|18689611}}</ref> [[Sympathomimetic]] PRC200-SS is the [[PRC050]] [[eutomer]],<ref name=Shaw>{{Cite pmid|17109850}}</ref> whereas PRC201 is the [[distomer]]. These compounds are preceded by [[venlafaxine]], which [[Wyeth]] claims is the first [[SNRI]].<ref>{{Cite pmid|9871604}}</ref> Venlafaxine was originally 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.

[[Preclinical]] toxicology studies of PRC200-SS in [[Crab-eating macaque|cynomolgus monkeys]] showed dose proportional kidney toxicity,<ref name="pmid21258088">{{cite journal | vauthors = Guha M, Heier A, Price S, Bielenstein M, Caccese RG, Heathcote DI, Simpson TR, Stong DB, Bodes E | display-authors = 6 | title = Assessment of biomarkers of drug-induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor | journal = Toxicological Sciences | volume = 120 | issue = 2 | pages = 269–83 | date = April 2011 | pmid = 21258088 | doi = 10.1093/toxsci/kfr013 | doi-access = free }}</ref> precluding any further [[drug development]].

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

==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,<ref name=Shaw/> venlafaxine is racemic;

PRC050 was further resolved into its constituent enantiomers, PRC200 (SS) and PRC201 (RR), respectively.<ref name=Liang/>

[[Image:PRCtwohundred.png|400px|left]]

{| class="wikitable" border="1" <caption>MAT of venlafaxine (Efexor) and PRC analogs (nM)</caption>

|-

! 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 transporter|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.<ref name=Liang/>

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

However, PRC200-SS is much more potent than imipramine: 1 mg/kg of PRC200-SS is ≈ equivalent to 15 mg/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 10 mg/kg does not enhance the activity of PRC200-SS further, indicating that 5 mg/kg is the opimal dosage.

==Toxicity==

Trials of PRC200-SS in [[Crab-eating Macaque|cynomolgus monkeys]] showed dose proportional kidney toxicity, with signs that the compound was damaging to the [[distal tubule]] and [[collecting duct]].<ref name="pmid21258088">{{cite journal |author=Guha M, Heier A, Price S, Bielenstein M, Caccese RG, Heathcote DI, Simpson TR, Stong DB, Bodes E |title=Assessment of Biomarkers of Drug-induced Kidney Injury in Cynomolgus Monkeys Treated with a Triple Re-uptake Inhibitor |journal=Toxicological Sciences : an Official Journal of the Society of Toxicology |volume= 120|issue= 2|pages= 269–83|year=2011 |month=January |pmid=21258088 |doi=10.1093/toxsci/kfr013 |url=}}</ref> This adverse result makes it unlikely that PRC200-SS will be developed for clinical use in humans, though development of related compounds may well continue.

==Microdialysis==

Concentrations of NE, 5-HT, DA, [[3,4-dihydroxyphenylacetic acid|DOPAC]], [[Homovanillic acid|HVA]], and [[5-hydroxyindolacetic acid|5-HIAA]], were measured in the mPFC and NAc, respectively.<ref name=Liang/>

At 10 mg/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 10 mg/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.

{| class="wikitable"

|-

|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.<ref>{{cite doi|10.1021/jo00128a025}}</ref><ref>{{Cite doi|10.1021/jo00094a011}}</ref><ref>{{Cite doi|10.1021/jo9702148}}</ref>

[[File:PCarlier.png|600px]]

[[File:Wyeth.png|600px]]

==Patents==

== References ==

[[Category:Serotonin–norepinephrine–dopamine reuptake inhibitors]]

{{DEFAULTSORT:Serotonin-Noradrenaline-Dopamine Reuptake Inhibitor}}

[[Category:~~Monoamine~~ ~~reuptake inhibitors~~]]

[[Category:2-Naphthyl compounds]]

[[Category:Serotonin-norepinephrine-dopamine reuptake inhibitors]]

[[Category:Naphthalenes]]

[[Category:Amines]]

[[Category:~~Alcohols~~]]

[[Category:Secondary alcohols]]

[[Category:Abandoned drugs]]