Naphthylaminopropane (PAL-287) is an
experimental
An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into cause-and-effect by demonstrating what outcome occurs when ...
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
under investigation as of 2007 for the treatment of
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
and
stimulant
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
.
Naphthylisopropylamine acts as a non-
neurotoxic
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
releasing agent
A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the synapse, release of a monoamine neurotransmitter from the synapse, presynaptic neuron into the synapse, leading to an increase in the extracellular conc ...
of
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
, and
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
, with
EC50 values of 3.4 nM, 11.1 nM, and 12.6 nM, respectively.
It also has
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Partn ...
for the
5-HT2A,
5-HT2B, and
5-HT2C receptors (EC
50 values = 466 nM, 40 nM, and 2.3 nM, respectively),
and acts as a
full agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
at 5-HT
2B and as a
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic e ...
at 5-HT
2C, while its affinity for 5-HT
2A is probably too low to be significant.
In animal studies, naphthylisopropylamine was shown to reduce
cocaine
Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...
self-administration
Self-administration is, in its medical sense, the process of a subject administering a pharmacological substance to themself. A clinical example of this is the subcutaneous "self-injection" of insulin by a diabetic patient.
In animal experimentati ...
, yet produced relatively weak stimulant effects when administered alone, being a (much) lesser stimulant than
d-amphetamine
Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and c ...
for comparison.
Further research is now being conducted in primates to see if it will be a useful substitute for treating drug addiction in humans as well.
An important observation is that in behavioral studies, rodents would consistently self-administer selective norepinephrine and dopamine releasing agents such as d-amphetamine, yet compounds that also release serotonin like naphthylisopropylamine would not be self-administered.
In addition to the drugs (acute) effects on self-administration, all of the available evidence suggests that the locomotor activation caused by the majority of dopamine releasers is also dampened when the drugs also cause serotonergic release. In fact, PAL-287 causes no locomotor activation at all (although admittedly the tests were only after acute dosing).
The high affinity of PAL-287 for 5-HT
2C receptors meant that it functioned as a reliable anorectant and was being considered for this indication (i.e. weight loss). However, there were ultimately some concerns raised over the compounds affinity for 5HT
2B receptors, since some of the more serious side effects of the serotonin releasing weight loss drug
fenfluramine
Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212102s003lb ...
were linked to an activation of this receptor.
Apparently, more research will have to be done to assess if PAL-287 causes activation of the 5HT
2A and 5HT
2B receptors in vivo. However, according to the authors, even the relatively safe drug MDMA causes heart disease,
and the incidence being reported for fenfluramine was not that great, even though the evidence being presented was indisputable.
Thus it is relatively more likely that any of the more serious side effects from using PAL-287 will only occur in cases of overdose, and not when using a clinically responsible amount of the drug.
See also
*
5-APDI
*
6-APT
6-(2-Aminopropyl)tetralin (6-APT), also sometimes called tetralinylaminopropane (TAP), is a drug of the amphetamine class which acts as a selective serotonin releasing agent (SSRA). It has IC50 values of 121 nM, 6,436 nM, and 3,371 nM for inhib ...
*
HDEP-28
HDEP-28 or ethylnaphthidate is a piperidine based stimulant drug, closely related to ethylphenidate, but with the benzene ring replaced by naphthalene. It is even more closely related to HDMP-28, which acts as a potent serotonin–norepinephrineâ ...
*
HDMP-28
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 methylphenidat ...
*
Methamnetamine
Methamnetamine (also known as methylnaphetamine, MNA, MNT and PAL-1046) is a triple monoamine releasing agent and ''N''-methyl analog of the non-neurotoxic experimental drug naphthylaminopropane and the naphthalene analog of methamphetamine. It ...
, N-methyl analogue, codenamed "MY-10" according to (Table 2).
*
Naphyrone
Naphyrone, also known as O-2482 and naphthylpyrovalerone, is a substituted cathinone drug derived from pyrovalerone that acts as a triple reuptake inhibitor, producing stimulant effects and has been reported as a novel designer drug. No safe ...
References
{{Phenethylamines
Amines
2-Naphthyl compounds
Serotonin receptor agonists
Serotonin-norepinephrine-dopamine releasing agents
Stimulants
Designer drugs
Entactogens and empathogens