Edoardo Marovino (a) , Ludovica Caprioli (b) Filippo Savi (c)

a Pharmacist, department of drug sciences, university of Pavia

b Department of chemistry, university of Pavia

c Department of medicine and surgery, university of Pavia

corresponding author: edoardo marovino (edoardo.marovino01@universitadipavia.it)

ABSTRACT

Psychostimulants, especially cocaine and amphetamines, are the most widely consumed illicit substances in the world after cannabinoids. They have always been known to be toxic substances whose use in both acute and chronic conditions involves significant mental and physical problems. However, their basic chemical structure, with appropriate modifications, has made it possible to produce drugs that can be used in diagnostics and therapy. In recent years various substances have seen contemporary applications both in the toxicological and pharmacological fields, just think of cannabinoids or opioids. Psychostimulants are not usually considered at the forefront but also for them, in addition to illicit and harmful uses, there are possible therapeutic applications and we have described how molecular or administration modifications can make a difference. This should make us reflect on legislative and ethical aspects for research and use in clinical practice.

INTRODUCTION

Psychostimulants are substances with sympathomimetic action which act by increasing monoaminergic neurotransmission in the central nervous system, thus enhancing serotonergic, dopaminergic and noradrenergic activity. We can distinguish substances of natural origin such as cocaine, an alkaloid deriving from the leaves of the Andean plant of erythroxylum coca or cainone, a monoamine alkaloid similar to ephedrine and deriving from the khat plant; to these are added synthetic substances initially used for therapeutic and research purposes and which over the years have been illegally reproduced in laboratories for recreational and illicit use. These include amphetamines, methamphetines (including substances such as ecstasy (MDMA, methylenedioxymethamphetamine)) and, more recently, substances belonging to the "NPS" (new psychoactive substances such as cathinones, piperazines, ketamine derivatives, etc … ). In general, however, all these compounds have common clinical characteristics, the ability to induce increased alertness, hyperactivity, and altered mood, and in addition can affect the cardiovascular system, ocular system, and disrupt temperature control.In the context of illicit uses, stimulants are among the most common substances used. As with many substances, psychostimulants can also be used for therapeutic purposes in some clinical conditions, both by naturally exploiting the molecules as such (see for example ephedrine and other substances used as topical decongestants) and through chemical modifications to optimize the receptor binding, make it more selective and avoid some effects related to acute or chronic administration. In this article we will describe some molecules in terms of toxicology but also of possible or current therapeutic applications, starting from the molecular structure and evaluating their drug and toxicological potential.

Cocaine is one of the oldest substances consumed by man. Native to South America, it is extracted from the leaves of erythroxylum coca to be marketed as a powder for injected use or, more commonly, intranasal or smoked. The hydrochloride form is a crystalline compound, soluble in water, which acts both indirectly, blocking the cerebral transporters of monoamines and therefore increasing their pre-synaptic bioavailability, and directly, acting on the sodium channels in an inhibitory sense, acting as a vasoconstrictor and local anesthetic. It is then metabolized in the liver by cholinesterases to an inactive demethylated metabolite, benzoylecgonine, and to ecgonine methyl ester (image 1). A small part is excreted as such in the urine. The half-life of cocaine is short, about 1-2 days in the urine, but in the keratin matrix it is detectable in chronic use for several weeks or months. Cocaine is a methyl and benzoyl ester of ecgonine, a tertiary base. In particular it presents :

• a hydrophilic part bonded to the tertiary amino nitrogen atom

• a hydrophobic part given by the peripheral aromatic ring

• an ester bond that binds the aromatic residue to the rest of the molecule

• the piperidine ring is in a more stable "chair" conformation

image 1: cocaine chemical structure and metabolisms

image 2: cocaine pharmacophore. While it was originally thought that the 2β-carbomethoxy moiety interacted with the DAT through hydrogen bonding, subsequent research has indicated that electrostatic (ionic) interactions are the primary means of interactions with the DAT.

In addition to being known to be a psychoactive substance, associated with serious problems of addiction and abuse and cases of death from overdose, cocaine has been exploited for the synthesis of some drugs still used today in clinical practice. A cocaine analogue is an artificial construct of a novel chemical compound from cocaine's molecular structure, with the result product sufficiently similar to cocaine to display similarity in, but alteration to, its chemical function. We have a first example with a [123I] ioflupane ([123I] FP-CIT), a cocaine analogue where the ester bond between the aromatic ring and the tropane group is replaced with a direct carbon-carbon bond 

image 3: chemical structure of 123I-Ioflupane

It is a dopamine transporter antagonist (DAT) to which it binds with high affinity. DAT receptors are present in high concentrations in the presynaptic dopaminergic terminals, especially at the nigro-striatal level. Scintigraphy with [123I] FP-CIT therefore allows to evaluate the integrity of the dopaminergic system and represents a useful marker, for example, in the diagnosis of parkinsonisms. In particular, the main indication is the differential diagnosis between essential tremor and parkinsonism. In fact, in Parkinson's, neuronal loss is associated with that of transporters and scintigraphy shows uptake deficits in the basal ganglia. DAT is a sodium chloride–dependent transmembrane protein on the presynaptic dopaminergic nerve terminal that mediates the recovery of dopamine in the synaptic button after its stimulus-mediated exocytosis, resulting in both a recovery of material used for the subsequent neosynthesis of the neurotransmitter itself and avoiding excessive receptor stimulation once the stimulus itself has ended. (neuroprotective effect). 123I-FP-CIT is a radioiodinated cocaine analog. The physical half-life of 123I is 13 h, and the major g-ray from 123I decay has an energy of 159 keV. 123I-FP-CIT is taken up rapidly in the human striatum, and Images are usually obtained at 4 h after the injection. Still in the field of radiopharmaceuticals used in nuclear diagnostics, especially for research purposes, radioisotope-labeled cocaine analogues such as carbon-11 and fluorine-18 have been produced. Among the most recent compounds synthesized for this purpose we recall a magnetic nanoparticle (NP) that specifically targets dopaminergic neurons and allows DAT imaging with magnetic resonance imaging (MRI). The nanoparticle (namely, NP-DN) is composed of an iron oxide core and a polyethylene glycol (PEG) coating to which a DAT specific dopaminergic neurolabeler (DN) is conjugated. NP-DN displayed long-term stability with favorable hydrodynamic size and surface charge suitable for in vivo application. In vitro studies showed NP-DN was non-toxic, displayed specificity towards DAT-expressing neurons. Another example concerns the structure of local anesthetics, where chemical modifications have been made to the basic pharmacophore of cocaine to differentiate its receptor binding capacities, exploiting the reduction of sodium conductance and therefore the obstacle to the genesis of the action potential. All local anesthetics are weak bases with a lipophilic group to enter the cell. These drugs are divided into two groups: amino-esters and amino-amides, which are more abundant and known because they are used in dental practice. The derivatives of cocaine are esters, easily hydrolyzable since the tissues are rich in pseudocolinesterase, which break ester bonds; they are therefore inactivated more quickly. As for the chemical structure of these compounds, it is distinguished within the molecule:

– an aromatic and heterocyclic nucleus, with lipophilic and therefore hydrophobic characteristics;

– a hydrophilic part, consisting of a secondary or tertiary amino group.

These two portions are linked by an intermediate chain.

Compared to cocaine, amphetamines on the other hand are synthetic substances which, however, have gained a lot of popularity especially in group contexts such as discos, parties and recreational contexts in general. The basic structure of these compounds is (RS) -1-phenylpropan-2-amine, a synthetic analogue of the endogenous neurotransmitter phenylethylamine, biosynthesized by enzymatic decarboxylation of the amino acid phenylalanine. Amphetamines have anorectic and psychostimulant properties and have been used in various contexts including recreational use during World War II by soldiers to reduce fatigue to more recent drug addictions. While not inducing a true physical dependence, amphetamines cause acute intoxication, even very serious, with marked psychotic or anxiety symptoms, especially if co-taken with cocaine or other substances and by vein. These are indirect agonists of the monoaminergic systems, especially at the central level, since it acts both as a substrate of the dopamine transporter (DAT) with which it competes for transport from the synaptic space to the cytoplasm, thus increasing its concentration in the inter-synaptic wall, and as vesicular monoamine transporter inhibitor (VMAT), which by preventing the filling of synaptic vesicles by reversing the direction of transport of the aforementioned transporters, induces the release of neurotransmitters, in particular dopamine and noradrenaline. This causes an increase in their synaptic concentration. It has a fair inhibitory capacity towards monoamine oxidase (MAO). The half-life is generally short, of a few hours, and they are eliminated in the urine in a pH-dependent manner, more rapidly in the case of acidic urinary pH (hence the use of ammonium chloride as an antidote in intoxication). However, in recent years, drugs have been produced using their basic pharmacophore. Some of these were then withdrawn from the market precisely because of their additive properties and the risk of toxicity (see the case of sibutramine and other anorectics) but others are still in use. For example, some first and second generation antidepressants have an amphetamine pharmacophoric structure; as a representative, we will describe a couple of them. Bupropion (image 4), also known as amphebutamone (or β-keto-3-chloro-N-tert-butylamphetamine) is a drug belonging to the cathinone substitute family (β-ketoamphetamine) used as an antidepressant, in the therapy of obesity, in the cessation of smoke. Bupropion is believed to exert its pharmacological action by inhibiting the reuptake of dopamine and noradrenaline. Having a psychostimulating activity it is particularly suitable for depressive forms in which hypersomnia, asthenia, cognitive dysfunctions and anhedonia prevail. Furthermore, acting as an antagonist of nicotinic acetylcholine receptors, it is exploited as a support in the cessation of cigarette smoking, since it decreases the craving and pleasure induced by nicotine. It has a mild anorectic effect. In Italy it is marketed as an aid to smoking cessation in the pharmaceutical form of 150 mg tablets while it is marketed as an antidepressant, in modified release tablets of 150 mg and 300 mg.

image 4: chemical structure of bupropion

Another example is given by trazodone, an antidepressant of the piperazine class, commonly used especially in the elderly with a peculiar mechanism of action. Trazodone inhibits the reuptake of serotonin but has a much lower affinity for the serotonin transporter (SERT) than SSRI class drugs. The anxiolytic and antidepressant effects of trazodone may be due to the agonistic effects on the 5-HT1A receptor and the antagonistic effects on the 5-HT2A and 5-HT2C receptors. The sedative-hypnotic effects may derive from its strong antagonistic activity at the level of the 5-receptors. HT2A and the α1-adrenergic receptor in addition to its moderate antagonistic activity at the H1 receptor.The drug is extensively metabolized, and 3 or 4 major metabolites, such as 2-methyl-4-chlorophenoxypropionic acid (mCPP), have been identified in the human body , which could be responsible for the side effects. The meta isomer of Chlorophenylpiperazine is in fact part of piperazine and its use can cause anxiety, mental confusion, tremors, panic attacks, migraines, increased sensitivity to light and noise. MCPP is also the main metabolite of the antidepressant drug Trazodone. Amphetamine are also used as such in therapy for attention deficit hyperactivity syndrome (ADHD) and narcolepsy. Drugs such as methylphenidate, modafinil and dextroamphetamine have also been approved for years for use in children, to which are added more recent compounds such as mazindol, which has a pharmacological activity profile similar to that of amphetamines but which differs from these. the latter both structurally and due to a lower stimulation activity of the central nervous system (CNS). Methylphenidate is marketed in Italy in tablets of 5 to 40 milligrams, both with immediate and prolonged release. It is subject to a tracing recipe, being a narcotic in table A, and it is precisely a sympathomimetic with a central action. It is indicated for ADHD (a behavioral syndrome characterized by symptoms that may include a chronic history of time-limited attention, distractibility, emotional lability, impulsivity, moderate to severe hyperactivity, secondary neurological signs and abnormal EEG) in children from from 6 years of age, if the corrective remedies alone have proved insufficient. Treatment with methylphenidate is not indicated in all children with ADHD and the decision to use the medicine must be based on a very thorough assessment of the severity and chronicity of the child's symptoms, in relation to his age. Due to its cardiovascular toxicity linked to sympathetic stimulation it is contraindicated in the presence of some heart diseases and requires periodic monitoring of blood pressure and heart rate, as well as frequent psychiatric re-evaluation for possible complications on mood and anxious or psychotic type.Methylphenidate binds to transporters synaptic for dopamine (DAT) and, to a lesser extent, for norepinephrine, thereby inhibiting the Presynaptic reuptake of dopamine. The subsequent increase in extracellular concentration and dopaminergic neurotransmission e noradrenergic is found in the prefrontal cortex, in the nucleus accumbens, in the striatum. More recently it has been found that high doses of MPH facilitate synaptic mediated transmission NMDA receptors with an independent mechanism, suggesting a greater complexity of the drug's mechanism of action. Among effects of methylphenidate are reported the increase or the maintaining alertness, reducing fatigue, the improved attention.

CONCLUSIONS

Psychostimulants are among the most widely used classes of illicit compounds and have now clearly surpassed heroin and reached equal merit for cannabinoids, especially among the youngest. However, as often happens in medicine, it has been possible to exploit some toxicodynamic or kinetic side effects to create compounds that can be used in therapy or diagnostics in a safer and more controlled way. For both the analogues of cocaine and amphetamines we have described, for the sake of brevity, only some of the compounds created and used, both because some have been withdrawn from the market for intolerability, and because others are for now only experimental; however it is certainly an interesting field of research. This is borne out, for example, by the recent marketing of esketamine, as well as the experimentation of similar molecules of psillocybin and mescaline.

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