Naphthylisopropylamine
Encyclopedia
Naphthylisopropylamine (PAL-287) is an experimental drug
currently under investigation for the treatment of alcohol
and stimulant
addiction.
Naphthylisopropylamine acts as a non-neurotoxic releasing agent
of serotonin
, norepinephrine
, and dopamine
, with EC50
values of 3.4 nM, 11.1 nM, and 12.6 nM, respectively. It also has affinity for the 5-HT2A
, 5-HT2B
, and 5-HT2C receptors (EC50 values = 466 nM, 40 nM, and 2.3 nM, respectively), and acts as a full agonist at 5-HT2B and as a partial agonist
at 5-HT2C, while its affinity for 5-HT2A is probably too low to be significant.
In animal studies, naphthylisopropylamine was shown to reduce cocaine
self-administration
, yet produced relatively weak stimulant effects when administered alone, being a (much) lesser stimulant than d-amphetamine 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 5HTergic release. In actual 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-HT2C 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 5HT2B receptors, since some of the more serious side effects of the serotonin releasing weight loss drug fenfluramine
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 5HT2A and 5HT2B 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.
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
currently under investigation for the treatment of alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
and stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
addiction.
Naphthylisopropylamine acts as a non-neurotoxic releasing agent
Releasing agent
A releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, and 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...
, with EC50
EC50
The term half maximal effective concentration refers to the concentration of a drug, antibody or toxicant which induces a response halfway between the baseline and maximum after some specified exposure time...
values of 3.4 nM, 11.1 nM, and 12.6 nM, respectively. It also has affinity for the 5-HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
, 5-HT2B
5-HT2B receptor
5-hydroxytryptamine receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.-Function:...
, and 5-HT2C receptors (EC50 values = 466 nM, 40 nM, and 2.3 nM, respectively), and acts as a full agonist at 5-HT2B and as a partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
at 5-HT2C, while its affinity for 5-HT2A is probably too low to be significant.
In animal studies, naphthylisopropylamine was shown 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...
self-administration
Self-administration
Self-administration is, in its medical sense, the process of a subject administering a pharmacological substance to him-, her-, or itself. A clinical example of this is the subcutaneous "self-injection" of insulin by a diabetic patient....
, yet produced relatively weak stimulant effects when administered alone, being a (much) lesser stimulant than d-amphetamine 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 5HTergic release. In actual 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-HT2C 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 5HT2B receptors, since some of the more serious side effects of the serotonin releasing weight loss drug fenfluramine
Fenfluramine
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication . Fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine...
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 5HT2A and 5HT2B 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-APDB
- 6-APB6-APB6-benzofuran or 1-benzofuran-6-ylpropan-2-amine is thought to be a stimulant and entactogen drug although to date, no authoritative source can say even whether or not it is psychoactive. Chemically, it is of the phenethylamine and substituted amphetamine classes...
- 6-APDB6-APDB6--2,3-dihydrobenzofuran is a stimulant and entactogen drug of the phenethylamine and amphetamine classes. It is an analogue of MDA where the heterocyclic 4-position oxygen from the 3,4-methylenedioxy ring has been replaced with a methylene group...
- 5-(2-Aminopropyl)indole5-(2-Aminopropyl)indole5-indole is an indole derivative which is mentioned in TIHKAL as a fairly potent and long-lasting stimulant drug. It is related to several well known drugs, and can be viewed both as a structural isomer of α-MT , and as a ring-substituted derivative of amphetamine...
- EthylenedioxymethamphetamineEDMA3,4-Ethylenedioxy-N-methylamphetamine is an entactogen drug of the amphetamine class. It is an analogue of MDMA where the methylenedioxy ring has been replaced by an ethylenedioxy ring. EDMA was first synthesized by Alexander Shulgin. In his book PiHKAL, the dosage is listed as 150–250 mg,...
- IndanylaminopropaneIndanylaminopropaneIndanylaminopropane , sometimes incorrectly referred to as indanylamphetamine, is an entactogen and psychedelic drug of the phenethylamine and amphetamine classes...
- TetralinylaminopropaneTetralinylaminopropaneTetralinylaminopropane is an entactogen drug of the amphetamine class which acts as a selective serotonin releasing agent . It has IC50 values of 121 nM, 6,436 nM, and 3,371 nM for inhibiting the reuptake of serotonin, dopamine, and norepinephrine, respectively...
- Naphyrone