Substituted phenylmorpholines, or substituted phenmetrazines alternatively, are chemical derivatives of phenylmorpholine or of the psychostimulant drug phenmetrazine. Most such compounds act as releasers of monoamine neurotransmitters, and have stimulant effects. Some also act as agonists at serotonin receptors, and compounds with an N-propyl substitution act as dopamine receptor agonists. A number of derivatives from this class have been investigated for medical applications, such as for use as anorectics or medications for the treatment of ADHD. Some compounds have also become subject to illicit use as designer drugs. [1] [2] [3] [4]
Substance | Structure | CAS number |
---|---|---|
2-phenylmorpholine | 23972-41-0 | |
2-phenyl-3-methylmorpholine (phenmetrazine) | 134-49-6 | |
2-phenyl-3,4-dimethylmorpholine (phendimetrazine) | 634-03-7 | |
2-phenyl-5-methylmorpholine (isophenmetrazine) | 80123-66-6 | |
2-phenyl-3-ethylmorpholine (phenetrazine) | 100368-98-7 | |
2-phenyl-3-methyl-4-ethylmorpholine (phenmetetrazine) | 92196-09-3 | |
2-phenyl-3,5-dimethylmorpholine (PDM-35) | 1218345-44-8 | |
2-phenyl-3,6-dimethylmorpholine (6-methylphenmetrazine, 3,6-DMPM) | 92902-99-3 | |
2-phenyl-5,5-dimethylmorpholine (G-130) | 42013-48-9 | |
2-phenyl-3-methylmorpholin-5-one (fenmetramide) | 5588-29-4 | |
4-isopropyl-2-phenylmorpholine [5] | 23222-62-0 | |
Fenbutrazate | 4378-36-3 | |
Morazone | 6536-18-1 | |
2-Fluorophenmetrazine | 1533654-24-8 | |
3-fluorophenmetrazine (PAL-593) | 1350768-28-3 | |
4-Fluorophenmetrazine (PAL-748) | 1097796-73-0 | |
3-fluorophenetrazine | ||
3-chlorophenmetrazine (PAL-594) | 1097796-78-5 | |
3-Methoxyphenmetrazine | ||
2-Methylphenmetrazine | 1507705-48-7 | |
3-methylphenmetrazine (PAL-773) | 1350768-41-0 | |
4-methylphenmetrazine (PAL-747) | 1998216-41-3 | |
4-methylphendimetrazine | 1445576-23-7 | |
3,4-Methylenedioxyphenmetrazine [6] | ||
Naphthylmetrazine (PAL-704) | ||
2-(thiophen-2-yl)-3-methylmorpholine | ||
2-(2,5-dimethoxy-4-bromophenyl)morpholine [7] | ||
2-(3-(Trifluoromethyl)phenyl)morpholine (flumexadol) [8] | 30914-89-7 | |
Oxaflozane | 26629-87-8 | |
Phenmetrazol | 1350768-19-2 | |
N-Ethylphenmetrazol | 97630-98-3 | |
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol (radafaxine) | 106083-71-0 | |
(2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethylmorpholin-2-ol (manifaxine) | 135306-39-7 | |
PF-219,061 [9] | 710654-74-3 | |
PF-592,379 | 710655-15-5 | |
OSU-6162 | 156907-84-5 | |
Compound 8 [10] | ||
2-Methyl-3-phenylpiperidine | 70769-67-4 | |
2-Phenyl-3-methyl-thiomorpholine | ||
Picilorex | 62510-56-9 | |
Butyltolylquinuclidine | ||
3-benzylmorpholine (3-BZM) [11] | 7684-27-7 | |
3-Benzhydrylmorpholine (3-BZHM) | 93406-27-0 | |
3,4-Methylenedioxyamphetamine is an empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.
2C-B-FLY is a psychedelic phenethylamine and designer drug of the 2C family. It was first synthesized in 1996 by Aaron Monte, Professor of Chemistry at UW-La Crosse.
The 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 (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.
A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. 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.
(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.
A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.
RTI-126 is a phenyltropane derivative which acts as a potent monoamine reuptake inhibitor and stimulant drug, and has been sold as a designer drug. It is around 5 times more potent than cocaine at inhibiting monoamine reuptake in vitro, but is relatively unselective. It binds to all three monoamine transporters, although still with some selectivity for the dopamine transporter. RTI-126 has a fast onset of effects and short duration of action, and its pharmacological profile in animals is among the closest to cocaine itself out of all the drugs in the RTI series. Its main application in scientific research has been in studies investigating the influence of pharmacokinetics on the abuse potential of stimulant drugs, with its rapid entry into the brain thought to be a key factor in producing its high propensity for development of dependence in animals.
A serotonin–dopamine releasing agent (SDRA) is a type of drug which induces the release of serotonin and dopamine in the body and/or brain.
Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.
4-Substituted-2,5-dimethoxyamphetamines (DOx) is a chemical class of substituted amphetamine derivatives featuring methoxy groups at the 2- and 5- positions of the phenyl ring, and a substituent such as alkyl or halogen at the 4- position of the phenyl ring. Most compounds of this class are potent and long-lasting psychedelic drugs, and act as highly selective 5-HT2A, 5-HT2B, and 5-HT2C receptor partial agonists. A few bulkier derivatives such as DOAM have similarly high binding affinity for 5-HT2 receptors but instead act as antagonists, and so do not produce psychedelic effects though they retain amphetamine-like stimulant effects.
6-APB is an empathogenic psychoactive compound of the substituted benzofuran and substituted phenethylamine classes. 6-APB and other compounds are sometimes informally called "Benzofury" in newspaper reports. It is similar in structure to MDA, but differs in that the 3,4-methylenedioxyphenyl ring system has been replaced with a benzofuran ring. 6-APB is also the unsaturated benzofuran derivative of 6-APDB. It may appear as a tan grainy powder. While the drug never became particularly popular, it briefly entered the rave and underground clubbing scene in the UK before its sale and import were banned. It falls under the category of research chemicals, sometimes called "legal highs." Because 6-APB and other substituted benzofurans have not been explicitly outlawed in some countries, they are often technically legal, contributing to their popularity.
Substituted tryptamines, or serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino (NH2) group via an ethyl (−CH2–CH2−) sidechain. In substituted tryptamines, the indole ring, sidechain, and/or amino group are modified by substituting another group for one of the hydrogen (H) atoms.
A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.
25CN-NBOH is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. This compound is notable as one of the most selective agonist ligands for the 5-HT2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT2A receptor and with 100x selectivity for 5-HT2A over 5-HT2C, and 46x selectivity for 5-HT2A over 5-HT2B. A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to 5-HT2 receptors and autoradiography.
5-Chloro-α-methyltryptamine (5-Chloro-αMT), also known as PAL-542, is a tryptamine derivative related to α-methyltryptamine (αMT) and one of only a few known specific serotonin-dopamine releasing agents (SDRAs). It has been investigated in animals as a potential treatment for cocaine dependence. The EC50 values of 5-chloro-αMT in evoking the in vitro release of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in rat synaptosomes were reported as 16 nM, 54 nM, and 3434 nM, with an NE/DA ratio of 63.6 and a DA/5-HT ratio of 3.38, indicating that it is a highly specific and well-balanced SDRA. However, 5-chloro-αMT has also been found to act as a potent full agonist of the 5-HT2A receptor, with an EC50 value of 6.27 nM and an efficacy of 105%, and almost assuredly acts as a potent agonist of other serotonin receptors as well.
3-Fluorophenmetrazine is a phenylmorpholine-based stimulant and fluorinated analogue of phenmetrazine that has been sold online as a designer drug.
4-Methylphenmetrazine is a recreational designer drug with stimulant effects. It is a substituted phenylmorpholine derivative, closely related to better known drugs such as phenmetrazine and 3-fluorophenmetrazine. It was first identified in Slovenia in 2015, and has been shown to act as a monoamine releaser with some preference for serotonin release.