1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine

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1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine
1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine structure.png
Identifiers
  • (3S,4S)-4-(4-Chloro-phenyl)-1-methyl-3-propyl-piperidine
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C15H22ClN
Molar mass 251.80 g·mol−1
3D model (JSmol)
  • CCC[C@@H]1CN(CC[C@@H]1C2=CC=C(C=C2)Cl)C
  • InChI=1S/C15H22ClN/c1-3-4-13-11-17(2)10-9-15(13)12-5-7-14(16)8-6-12/h5-8,13,15H,3-4,9-11H2,1-2H3/t13-,15-/m1/s1
  • Key:MWGRXFWGMDSMNI-UKRRQHHQSA-N

1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine is a drug developed by a team led by Alan Kozikowski, which acts as a potent dopamine reuptake inhibitor, and was developed as a potential therapeutic agent for the treatment of cocaine addiction. [1] As with related compounds such as nocaine, it is a structurally simplified derivative of related phenyltropane compounds. [2] Its activity at the serotonin and noradrenaline transporters has not been published, though most related 4-phenylpiperidine derivatives are relatively selective for inhibiting dopamine reuptake over the other monoamine neurotransmitters. While several of its isomers are active, the (3S,4S)-enantiomer is by far the most potent. [3] [4] The rearranged structural isomer 2-[1-(4-chlorophenyl)butyl]piperidine is also a potent inhibitor of dopamine reuptake. [5]

2-[1-(4-chlorophenyl)butyl]piperidine 2-(1-(4-chlorophenyl)butyl)piperidine structure.png
2-[1-(4-chlorophenyl)butyl]piperidine

See also

Related Research Articles

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

<span class="mw-page-title-main">Phenyltropane</span> Class of chemical compounds

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

<span class="mw-page-title-main">(+)-CPCA</span> Stimulant drug

(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine lacks the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

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

Troparil is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.

<i>N</i>,<i>O</i>-Dimethyl-4-(2-naphthyl)piperidine-3-carboxylate Chemical compound

N,O-Dimethyl-4β-(2-naphthyl)piperidine-3β-carboxylate (DMNPC) is a piperidine based stimulant drug which is synthesised from arecoline. It is similar to nocaine in chemical structure, and has two and a half times more activity than cocaine as a dopamine reuptake inhibitor. However it is also a potent serotonin reuptake inhibitor, with similar affinity to fluoxetine.

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

Dichloropane ((−)-2β-Carbomethoxy-3β-(3,4-dichlorophenyl)tropane, RTI-111, O-401) is a stimulant of the phenyltropane class that acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) with IC50 values of 3.13, 18, and 0.79 nM, respectively. In animal studies, dichloropane had a slower onset and longer duration of action compared to cocaine.

<span class="mw-page-title-main">HDMP-28</span> Stimulant drug

HDMP-28 or methylnaphthidate is a piperidine based stimulant drug, closely related to methylphenidate, but with the benzene ring replaced by naphthalene. It is a potent dopamine reuptake inhibitor, with several times the potency of methylphenidate and a short duration of action, and is a structural isomer of another potent dopamine reuptake inhibitor, N,O-Dimethyl-4-(2-naphthyl)piperidine-3-carboxylate. It has been sold as a designer drug since around 2015.

<span class="mw-page-title-main">2-Benzylpiperidine</span> Chemical compound

2-Benzylpiperidine is a stimulant drug of the arylpiperidine family. It is similar in structure to certain other stimulants such as methylphenidate and desoxypipradrol. However, it is far less potent as a monoamine reuptake inhibitor in comparison. The drug is little used as a stimulant, with its main use being as a synthetic intermediate in the manufacture of other drugs.

<span class="mw-page-title-main">RTI-126</span> Pharmaceutical drug

RTI-126 is a phenyltropane derivative which acts as a potent monoamine reuptake inhibitor and stimulant drug, and has been sold as a designer drug. It is around 5 times more potent than cocaine at inhibiting monoamine reuptake in vitro, but is relatively unselective. It binds to all three monoamine transporters, although still with some selectivity for the dopamine transporter. RTI-126 has a fast onset of effects and short duration of action, and its pharmacological profile in animals is among the closest to cocaine itself out of all the drugs in the RTI series. Its main application in scientific research has been in studies investigating the influence of pharmacokinetics on the abuse potential of stimulant drugs, with its rapid entry into the brain thought to be a key factor in producing its high propensity for development of dependence in animals.

<span class="mw-page-title-main">RTI-336</span> Chemical compound

RTI(-4229)-336, is a phenyltropane derivative which acts as a potent and selective dopamine reuptake inhibitor and stimulant drug. It binds to the dopamine transporter with around 20x the affinity of cocaine, however it produces relatively mild stimulant effects, with a slow onset and long duration of action. These characteristics make it a potential candidate for treatment of cocaine addiction, as a possible substitute drug analogous to how methadone is used for treating heroin abuse. RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration, and significantly reduces rates of cocaine use, especially when combined with SSRIs, and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.

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

Tropoxane (O-1072) is an aryloxytropane derivative drug developed by Organix Inc., which acts as a stimulant and potent dopamine and serotonin reuptake inhibitor. It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link, demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.

<span class="mw-page-title-main">O-2172</span> Chemical compound

O-2172 is a drug developed by Organix Inc, which acts as a stimulant and potent dopamine reuptake inhibitor. It is an analogue of methylphenidate where the phenyl ring has had a 3,4-dichloro substitution added, and the piperidine ring has been replaced by cyclopentane. It is around 1/3 the potency of methylphenidate, demonstrating that even with the important binding group of the nitrogen lone pair removed entirely, selective DAT binding and reuptake inhibition is still possible.

<span class="mw-page-title-main">RTI-113</span> Chemical compound

RTI(-4229)-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine." Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.

<span class="mw-page-title-main">RTI-31</span> Chemical compound

(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-4229-31) is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article, RTI-31 is 64 times the strength of cocaine in terms of its potency to elicit self-administration in monkeys. WIN 35428 was 6 times weaker than RTI-31, whereas RTI-51 was 2.6 times weaker than RTI-31.

<span class="mw-page-title-main">RTI-51</span> Chemical compound

(–)-2β-Carbomethoxy-3β-(4-bromophenyl)tropane is a semi-synthetic alkaloid in the phenyltropane group of psychostimulant compounds. First publicized in the 1990s, it has not been used enough to have gained a fully established profile. RTI-51 can be expected to have properties lying somewhere in between RTI-31 and RTI-55. It has a ratio of monoamine reuptake inhibition of dopamine > serotonin > norepinephrine which is an unusual balance of effects not produced by other commonly used compounds. It has been used in its 76Br radiolabelled form to map the distribution of dopamine transporters in the brain.

<span class="mw-page-title-main">JZ-IV-10</span> Chemical compound

JZ-IV-10 is a piperidine derivative related to cocaine which acts as a highly potent serotonin–norepinephrine–dopamine reuptake inhibitor. The eugeroic modafinil was used as a lead to fuel this compound's discovery.

<span class="mw-page-title-main">RTI-83</span> Chemical compound

RTI-83 is a phenyltropane derivative which represents a rare example of an SDRI or serotonin-dopamine reuptake inhibitor, a drug which inhibits the reuptake of the neurotransmitters serotonin and dopamine, while having little or no effect on the reuptake of the related neurotransmitter noradrenaline. With a binding affinity (Ki) of 55 nM at DAT and 28.4 nM at SERT but only 4030 nM at NET, RTI-83 has reasonable selectivity for DAT/SERT over NET

References

  1. US 6180648,Kozikowski AP, Araldi GL,"Analogs of cocaine",issued 2001-01-30, assigned to George Town University
  2. Kozikowski AP, Araldi GL, Prakash KR, Zhang M, Johnson KM (December 1998). "Synthesis and biological properties of new 2beta-alkyl- and 2beta-aryl-3-(substituted phenyl)tropane derivatives: stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters". Journal of Medicinal Chemistry. 41 (25): 4973–82. doi:10.1021/jm9802564. PMID   9836615.
  3. Kozikowski AP, Araldi GL, Boja J, Meil WM, Johnson KM, Flippen-Anderson JL, George C, Saiah E (May 1998). "Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton". Journal of Medicinal Chemistry. 41 (11): 1962–9. CiteSeerX   10.1.1.512.7158 . doi:10.1021/jm980028+. PMID   9599245.
  4. US 6440996,Kozikowski AP, Araldi GL, Tamiz AP,"Monomeric and dimeric heterocycles, and therapeutic uses thereof",issued 2002-08-27, assigned to Georgetown University
  5. Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A (January 2007). "Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter". Journal of Medicinal Chemistry. 50 (2): 219–32. doi:10.1021/jm0608614. PMID   17228864.
  6. CID 16102751 from PubChem