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.
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.
2β-Propanoyl-3β-(2-naphthyl)-tropane or WF-23 is a cocaine analogue. It is several hundred times more potent than cocaine at being a serotonin-norepinephrine-dopamine reuptake inhibitor.
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.
Difluoropine (O-620) is a stimulant drug synthesised from tropinone, which acts as a potent and selective dopamine reuptake inhibitor. Difluoropine is unique among the tropane-derived dopamine reuptake inhibitors in that the active stereoisomer is the (S) enantiomer rather than the (R) enantiomer, the opposite way round compared to natural cocaine. It is structurally related to benztropine and has similar anticholinergic and antihistamine effects in addition to its dopamine reuptake inhibitory action.
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.
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)-177 is a synthetic stimulant drug from the phenyltropane family, which acts as a DRI with micromolar affinity for the SERT. RTI-177 has an unusually long duration of action of 20 hours or more, substantially longer than the related compound RTI-336 from which it differs in molecular structure only by the absence of a p-methyl group.
(–)-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.
(–)-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. Importantly it has a ratio of monoamine reuptake inhibition of D > S > N 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.
4-Methylamphetamine is a stimulant and anorectic drug of the phenethylamine and amphetamine chemical classes.
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.
The alpha-3 beta-4 nicotinic receptor, also known as the α3β4 receptor and the ganglion-type nicotinic receptor, is a type of nicotinic acetylcholine receptor, consisting of α3 and β4 subunits. It is located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or presynaptic excitation, mainly by increased Na+ and K+ permeability.
2,3-Dichlorophenylpiperazine (2,3-DCPP or DCPP) is a chemical compound from the phenylpiperazine family. It is both a precursor in the synthesis of aripiprazole and one of its metabolites. It is unclear whether 2,3-DCPP is pharmacologically active as a serotonin receptor agonist similar to its close analogue 3-chlorophenylpiperazine (mCPP), though it has been shown to act as a partial agonist of the dopamine D2 and D3 receptors.
Difluoromethylenedioxyamphetamine (DiFMDA) is a substituted derivative of 3,4-methylenedioxyamphetamine (MDA), which was developed by Daniel Trachsel and coworkers, along with the corresponding fluorinated derivatives of MDMA, MDEA, BDB and MBDB, with the aim of finding a non-neurotoxic drug able to be used as a less harmful substitute for entactogenic drugs such as MDMA. Since a major route of the normal metabolism of these compounds is scission of the methylenedioxy ring, producing neurotoxic metabolites such as alpha-methyldopamine, it was hoped that the difluoromethylenedioxy bioisostere would show increased metabolic stability and less toxicity.
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
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, but also acts as a selective serotonergic neurotoxin in a similar manner to the related para-chloroamphetamine, though with slightly lower potency. It is also a monoamine oxidase inhibitor (MAOI), 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.
S32212 is a drug which is under preclinical investigation as a potential antidepressant medicine. It behaves as a selective, combined 5-HT2C receptor inverse agonist and α2-adrenergic receptor antagonist (at all three subtypes—α2A, α2B, and α2C) with additional 5-HT2A and, to a lesser extent, 5-HT2B receptor antagonistic properties, and lacks any apparent affinity for the monoamine reuptake transporters or for the α1-adrenergic, H1, or mACh receptors. This profile of activity is compatible with the definition of a noradrenergic and specific serotonergic antidepressant (NaSSA), and as such, S32212 could in turn be classified as a NaSSA if it reaches the market.
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.
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