Phenyltropanes were originally developed to reduce cocaine

Cocaine

Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

 addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake

Reuptake

Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....

 transporters

Neurotransmitter transporter

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations...

. Although RTI

RTI International

RTI International is the trade name of the Research Triangle Institute, an independent research institute established in 1958. The founding tenant of North Carolina’s Research Triangle Park, RTI was created as part of a larger effort to harness the intellectual capital of the area’s three major...

 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.

Addiction

The phenyltropane compounds were initially discovered by R. Clarke et al. during research to try and dissociate the stimulant properties of cocaine from its abuse and dependence liability. The first simple phenyltropanes to be made (WIN 35065-2 and WIN 34,428) were shown to be active in behavioral assays only for the ββ-isomers. The activity of the corresponding αβ-isomers was disappointing.

It was later shown that WIN 35065-2 and WIN 34,428 are mostly dopamine selective reuptake inhibitors with some residual actions at the NET

Norepinephrine transporter

The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....

 and SERT

Serotonin transporter

The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...

. This is in contrast to cocaine

Cocaine

Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

, which is a completely nonselective SNDRI. Given that other simple stimulant compounds such as amphetamines derive their mechanism of action through dopaminergic release, it would seem reasonable to presume that dopamine

Dopamine

Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 is the key neurotransmitter

Neurotransmitter

Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

 responsible for mediating the reinforcing (and hence addictive) actions of these drugs.

The dopamine hypothesis.

The role of the NET in mediating self-administration cannot be entirely ruled out.

The relationship between the affinity of a psychostimulant for the SERT and its ability to evoke self-administration is negative.

According to the graph, cocaine is ranked second only to heroin in terms of the physical harm that it does to the user. Given the high abuse and dependence liability that cocaine poses, it appears that there is an urgent need to develop substitute agonists that can help in curing this addiction. Agonist based therapies have been implemented successfully in the treatment of tobacco and heroin dependence, although no such medicine exists for the rehabilitation of stimulant abusers. It is true that SSRIs can reduce cocaine intake, although this would be a poor strategy in human addicts due to the fact that it would probably result in poor patient compliance and high rates of relapse.

Animal studies on monkeys and rats have tried to assess the self administration propensity of phenyltropane analogs alongside cocaine. Frequently the analogs are administered prior to the start of a session to see if they can suppress cocaine lever responding. Most of the analogs behave in ways that might be considered typical for a DRI. In particular, they tend to stimulate locomotor activity, and cause nonselective reductions in cocaine intake relative to food. At the dose that can reduce cocaine intake, most of the analogs require a high DAT occupancy. This would mean that the agonists would need to be behaviorally active at the dose that can bring about reductions in cocaine craving. Most of the analogs will readily substitute for cocaine, although most do not elicit as many lever responses per session because of pharmacokinetic factors. Since these agonists function as reinforcers, there is an obvious concern surrounding their abuse liability.

Nevertheless, a slow onset, long-duration agonist seems like a reasonable approach. Phenyltropanes are widely used in animal studies of drug addiction as they share the stimulant properties and reinforcing effects of cocaine, but with higher potency, less non-specific binding which avoids the cardiotoxicity

Cardiotoxicity

Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...

 associated with cocaine.

RTI-336 is an interesting example of a phenyltropane that is being explored in the context of a treatment for cocaine addiction. RTI-336 is a DRI and thus specifically targets the DAT which is responsible for the addictive properties of cocaine. The above statement about the DAT

Dopamine transporter

The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...

 is only true in so far as it has a magnified sense of importance in mediating the addictive properties, particularly of cocaine but also of psychostimulants in general. Nevertheless, in not wanting to oversimplify the situation too blindly, it needs to be addressed that the DAT is not the sole target of these drugs, in the case of reuptake inhibitors. It is obviously the case that dopamine is a biological precursor to noradenaline. DA is made from tyramine, which is made from tyrosine, which is a non-essential amino acid given that it can be made from phenylalanine

Phenylalanine

Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...

.

The more greatly attested habit creating methamphetamine is more serotonergic than the lesser reinforcing amphetamine. Most modern research suggests that 5-HT is negatively correlated with the addiction forming potential of psychostimulants, this is not saying that SRI properties cannot be considered beneficial. In fact, the above was proven by Rothman for releasing agents under the PAL-287 program of related molecules. What was somewhat interesting is that although the reason for the lack of reinforcement of RTI-112

RTI-112

RTI-112 is a synthetic stimulant drug from the phenyltropane family. In contrast to RTI-113 which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor....

 is now well established, closely related RTI-111 was able to behave in ways that might be typical for a nonselective SNDRI such as cocaine. The role of the NET is not completely deleterious. In a recent paper by Rothman on transporter substrates, he establishes that for releasers that are amphetamine-like, discrimination stimulus is more accurately dictated by NE release than DA release. This argument does not mitigate a case against the importance of DA, but is suggestive that catecholamine in general is important. the exact ratio being 50:50 in the case of methylphenidate.

Desipramine

Desipramine

Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...

 and atomoxetine are not reliably self-administered though, whereas most selective DRIs are. SSRIs are not self-administered either. Hence, it should be borne in mind that these neurotransmitters are unlikely to be involved in the addiction forming properties of cocaine and related stimulants. Nevertheless, they are still behaviorally active and will contribute to the effects that such drugs elicit in their users.

Promiscuity among transporters is worth bearing in mind. Monoamine transporters can transport neurotransmitters other than their "native" neurotransmitter. As an example, in the core (or shell?) of prefrontal cortex

Prefrontal cortex

The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...

 where DATs are low in number, DA is transported by the NET instead. Hence, selective NRIs such as atomoxetine are able to increase the concentration of supracellular (synaptic) DA in this brain region via NET blockade.

Weeding out SERT and NET affinity is desirable in the context that these molecular targets are less relevant to the goals of the treatment program, which is to reduce cocaine intake. It can be clearly seen that RTI-336 has fewer metabolically labile sites than cocaine, and therefore has a longer duration span.

Binding ligands

These compounds are primarily used in scientific research, as their high binding affinity

Dissociation constant

In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...

 for monoamine transporters, and the wide range of radiolabelled

Isotopic labeling

Isotopic labeling is a technique for tracking the passage of a sample of substance through a system. The substance is 'labeled' by including unusual isotopes in its chemical composition...

 phenyltropane compounds available with different binding specificities makes them very useful for mapping the distribution of the various monoamine transporters in the brain.

Other uses

Some phenyltropane derivatives have also been researched for medical use in the treatment of conditions such as Parkinson's Disease

Parkinson's disease

Parkinson's disease is a degenerative disorder of the central nervous system...

 and Alzheimer's Disease

Alzheimer's disease

Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

, depression

Depression (mood)

Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...

, and their strong appetite suppressant effects makes them promising candidates for facilitating weight loss in the treatment of obesity

Obesity

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

.

Transporter selectivity

Compounds are known with a pronounced selectivity for each MAT – dopamine

Dopamine transporter

The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...

, noradrenaline

Norepinephrine transporter

The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....

 and the serotonin transporter

Serotonin transporter

The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...

.

Phenyltropane based "SNDRI

Serotonin-noradrenaline-dopamine reuptake inhibitor

A serotonin–norepinephrine–dopamine reuptake inhibitor , or triple reuptake inhibitor , is a drug that acts simultaneously as a reuptake inhibitor for the monoamine neurotransmitters, serotonin , norepinephrine and dopamine , by blocking the action of the serotonin transporter , norepinephrine...

's" are another possibility.

Related compounds

Closely related compounds have a varied aryl

Aryl

In the context of organic molecules, aryl refers to any functional group or substituent derived from an aromatic ring, be it phenyl, naphthyl, thienyl, indolyl, etc....

 fragment, like naphthyl

Naphthalene

Naphthalene is an organic compound with formula . It is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromatic hydrocarbon, naphthalene's structure consists of a fused pair of benzene rings...

, or a varied tropane fragment like with exchanged heteroatom

Heteroatom

In organic chemistry, a heteroatom is any atom that is not carbon or hydrogen. Usually, the term is used to indicate that non-carbon atoms have replaced carbon in the backbone of the molecular structure...

, trop-2-enes, quinuclidine

Quinuclidine

Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with pKa of the conjugate acid of 11.0. This is due to greater availability of the nitrogen lone pair...

s, piperidine

Piperidine

Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...

s.