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ECHA InfoCard | 100.023.060 |
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Formula | C9H11Cl2N |
Molar mass | 204.09 g·mol−1 |
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3,4-Dichloroamphetamine (DCA), is an amphetamine derived drug invented by Eli Lilly in the 1960s, which has a number of pharmacological actions. It acts as a highly potent and selective serotonin releasing agent (SSRA) and binds to the serotonin transporter with high affinity, [1] [2] [3] [4] but also acts as a selective serotonergic neurotoxin in a similar manner to the related para-chloroamphetamine, though with slightly lower potency. [5] It is also a monoamine oxidase inhibitor (MAOI), [6] as well as a very potent inhibitor of the enzyme phenylethanolamine N-methyl transferase which normally functions to transform noradrenaline into adrenaline in the body. [7] [8]
The reaction of 3,4-Dichlorobenzyl Chloride [102-47-6] (1) with cyanide anion gives 3,4-Dichlorophenylacetonitrile [3218-49-3] (2). Reaction with sodium methoxide and ethylacetate gives Alpha-Acetoxy-3,4-Dichlorobenzeneacetonitrile, CID:14318103 (3). Removal of the nitrile group in the presence of sulfuric acid gives 3,4-Dichlorophenylacetone [6097-32-1] (4). Oxime formation with hydroxylamine gives N-[1-(3,4-dichlorophenyl)propan-2-ylidene]hydroxylamine, CID:74315855 (5). Reduction of the oxime completed the synthesis of 3,4-Dichloroamphetamine (6).
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these analogues. 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.
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.
Lobeline is a pyridine alkaloid found in a variety of plants, particularly those in the genus Lobelia, including Indian tobacco, Devil's tobacco, great lobelia, Lobelia chinensis, and Hippobroma longiflora. In its pure form, it is a white amorphous powder which is freely soluble in water.
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.
A reuptake inhibitor (RI) is a type of drug known as a reuptake modulator that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.
5-Methyl-3,4-methylenedioxyamphetamine (5-Methyl-MDA) is an entactogen and psychedelic designer drug of the amphetamine class. It is a ring-methylated homologue of MDA and a structural isomer of MDMA.
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.
MDAI (5,6-methylenedioxy-2-aminoindane) is a drug developed in the 1990s by a team led by David E. Nichols at Purdue University. It acts as a non-neurotoxic and highly selective serotonin releasing agent (SSRA) in vitro and produces entactogen effects in humans.
A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.
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.
(–)-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 x the strength of cocaine in terms of its potency to elicit self-administration in monkeys. WIN 35428 was 6 x weaker than RTI-31, whereas RTI-51 was 2.6 x weaker than RTI-31.
3-Methylamphetamine is a stimulant drug from the amphetamine family. It is self-administered by mice to a similar extent to 4-fluoroamphetamine and has comparable properties as a monoamine releaser, although with a more balanced release of all three monoamines, as opposed to the more dopamine/noradrenaline selective fluoro analogues.
6-Chloro-2-aminotetralin (6-CAT) is a drug which acts as a selective serotonin releasing agent (SSRA) and is a putative entactogen in humans. It is a rigid analogue of para-chloroamphetamine (PCA).
Amiflamine (FLA-336) is a reversible inhibitor of monoamine oxidase A (MAO-A), thereby being a RIMA, and, to a lesser extent, semicarbazide-sensitive amine oxidase (SSAO), as well as a serotonin releasing agent (SRA). It is a derivative of the phenethylamine and amphetamine chemical classes. The (+)-enantiomer is the active stereoisomer.
GSK1360707F is a potent and selective triple reuptake inhibitor. It is chemically related to amitifadine and NS-2359 (GSK-372,475). Until recently, it was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons.
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
1-Aminomethyl-5-methoxyindane (AMMI), is a drug developed by a team led by David E. Nichols at Purdue University, which acts as a selective serotonin releasing agent (SSRA) and binds to the serotonin transporter with similar affinity to DFMDA.
A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.
Pseudophenmetrazine is a psychostimulant compound of the morpholine class. It is the N-demethylated and cis-configured analogue of phendimetrazine as well as the cis-configured stereoisomer of phenmetrazine. In addition, along with phenmetrazine, it is believed to be one of the active metabolites of phendimetrazine, which itself is inactive and behaves merely as a prodrug. Relative to phenmetrazine, pseudophenmetrazine is of fairly low potency, acting as a modest releasing agent of norepinephrine (EC50 = 514 nM), while its (+)-enantiomer is a weak releaser of dopamine (EC50 = 1,457 nM) whereas its (−)-enantiomer is a weak reuptake inhibitor of dopamine (Ki = 2,691 nM); together as a racemic mixture with the two enantiomers combined, pseudophenmetrazine behaves overall more as a dopamine reuptake inhibitor (Ki = 2,630 nM), possibly due to the (+)-enantiomer blocking the uptake of the (−)-enantiomer into dopaminergic neurons and thus preventing it from inducing dopamine release. Neither enantiomer has any significant effect on serotonin reuptake or release (both Ki = >10,000 nM and EC50 = >10,000 nM, respectively).