Naphthylaminopropane (NAP; code name PAL-287), also known as naphthylisopropylamine (NIPA), 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 whe ...

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

of the

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

and naphthylaminopropane families that was under investigation for the treatment of

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

and

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

Pharmacology

Pharmacodynamics

Activities

Naphthylaminopropane is a

serotonin–norepinephrine–dopamine releasing agent A serotonin–norepinephrine–dopamine releasing agent (SNDRA), also known as a triple releasing agent (TRA), is a type of drug which induces the release of serotonin, norepinephrine/epinephrine, and dopamine in the brain and body. SNDRAs produc ...

(SNDRA). Its values for induction of monoamine release are 3.4nM for

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

, 11.1nM for

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

, and 12.6nM for

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. The drug is also an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Its values are 466nM at the serotonin 5-HT_2A receptor, 40nM at the serotonin 5-HT_2B receptor, and 2.3nM at the serotonin 5-HT_2C receptor. It is 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 agoni ...

of the serotonin 5-HT_2A and 5-HT_2B receptors and a weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the serotonin 5-HT_2C receptor ( = 20%). Naphthylaminopropane has been found to act as a potent

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative dea ...

(MAO-A)

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

, with an of 420nM. This is similar to the potency of the well-known MAO-A inhibitors ''para''-methoxyamphetamine (PMA) and

4-methylthioamphetamine 4-Methylthioamphetamine (4-MTA), also known as ''para''-methylthioamphetamine (MTA), is a designer drug of the substituted amphetamine class developed in the 1990s by a team led by David E. Nichols, an American pharmacologist and medical chemist ...

(4-MTA).

Effects

animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including art history, anthropology ...

, naphthylaminopropane was shown to reduce

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

self-administration Self-administration is, in its Medicine, medical sense, the process of a subject administering a Pharmacology, pharmacological substance to themself. A clinical example of this is the subcutaneous "self-injection" of insulin by a Diabetes, diabetic ...

, yet produced relatively weak

effects when administered alone, being a much less effective stimulant than

dextroamphetamine Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...

. Further research was being conducted in primates to see if the drug would be a useful substitute for treating

drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

in humans. An important observation is that in behavioral studies, rodents would consistently self-administer selective

norepinephrine–dopamine releasing agent A norepinephrine–dopamine releasing agent (NDRA) is a type of drug which induces the synapse, release of norepinephrine (and epinephrine) and dopamine in the body and/or brain. Many of these are amphetamine type stimulants. Examples Examples ...

s (NDRAs) like dextroamphetamine, yet compounds that also potently release

like naphthylaminopropane would not be self-administered. In addition to the drug's effects on self-administration, the available evidence suggests that the locomotor activation caused by dopamine releasers is also dampened when they additionally induce serotonin release. Notably, despite potent dopamine release induction, naphthylaminopropane produces weak or no locomotor activation in rodents. The high

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 Pa ...

of naphthylaminopropane for the serotonin 5-HT_2C receptor meant that it might function as an

appetite suppressant An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...

and was being considered for possible clinical use for this indication (i.e.,

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

). However, concerns were raised over the affinity of the drug for the serotonin 5-HT_2B receptor, 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. It was formerly used as an appetite suppressant in the treat ...

were linked to activation of this receptor. It is uncertain, although was considered unlikely per the researchers who developed the drug, that activation of the serotonin 5-HT_2A and 5-HT_2B receptors occurs to a significant degree ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

''.

Chemistry

Naphthylaminopropane was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

by 1939. The drug is also known as 2-naphthylaminopropane (2-NAP) or β-naphthylaminopropane, and it was described along with its

positional isomer In chemistry, a structural isomer (or constitutional isomer in the IUPAC nomenclature) of a compound is a compound that contains the same number and type of atoms, but with a different connectivity (i.e. arrangement of bonds) between them. The ...

1-naphthylaminopropane (1-NAP; α-naphthylaminopropane). Both 2-NAP and 1-NAP failed to substitute for

in rodent drug discrimination tests, suggesting that they lack

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

-like effects. The β-keto and ''N''-methyl analogue of 2-NAP has been assessed and was found to act as a potent SNDRA similarly to naphthylaminopropane. Naphthylaminopropane is structurally related to certain rigid analogues of

. Rigid amphetamine analogues include

2-aminotetralin 2-Aminotetralin (2-AT), also known as 1,2,3,4-tetrahydronaphthalen-2-amine (THN), is a stimulant drug with a chemical structure consisting of a tetralin core with an amine as substituent. 2-AT is a rigid analogue of phenylisobutylamine and ful ...

(2-AT), 2-amino-1,2-dihydronaphthalene (2-ADN), 1-phenylpiperazine (1-PP), 2-aminoindane (2-AI), , and . A few

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

s of naphthylaminopropane have been developed or have appeared, including methamnetamine (''N''-methylnaphthylaminopropane; MNAP; PAL-1046), ''N''-ethylnaphthylaminopropane (ENAP; PAL-1045), and BMAPN (βk-methamnetamine; β-keto-MNAP; 2-naphthylmethcathinone). Like naphthylaminopropane, these derivatives also act as potent

monoamine releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...

s, including of serotonin, norepinephrine, and/or dopamine.

References