AMPH is a phenylethylamine central nervous system stimulant that mainly exerts its effect by promoting the release of monoamine neurotransmitters such as dopamine and norepinephrine. As an important psychoactive substance, AMPH can be used to treat diseases such as attention deficit hyperactivity disorder (ADHD), but it is also classified as a controlled drug due to its addictive nature. In 1933, American chemist Gordon Alles first synthesized amphetamine. This discovery not only pioneered the research of amphetamine-like drugs but also provided an important tool for neuropharmacological studies. AMPH regulates the concentration of neurotransmitters in the synaptic space through specific interactions with membrane proteins such as the dopamine transporter (DAT). This mechanism has become a classic model for studying the release and reuptake of neurotransmitters and is of great significance for understanding the mechanism of drug addiction and developing therapeutic drugs for neurological diseases.
AMPH is a central nervous system stimulant with a molecular weight of 135.21 daltons (chemical formula C9H13N), and its molecular structure varies among different derivatives. Common derivative molecular weights: dextroamphetamine (135.21), methamphetamine (149.23), 3, 4-methylenedioxymethamphetamine (MDMA, 193.25). The structural differences are mainly reflected in: benzene ring substituents (methylamphetamine adds a methyl group), side chain modifications (MDMA adds a methylene dioxy group), etc. The AMPH molecule contains the basic skeleton of phenylethylamine, featuring a lipophilic benzene ring and a hydrophilic amino group, which makes it easy to pass through the blood-brain barrier. Its active center is a chiral β -carbon atom, and the pharmacological activity of the dextrorotatory form is significantly higher than that of the levorotatory form.
Fig. 1 AMPH induces overactivity through the non-IL-1 β pathway of the P2X7 receptor.1
Key structural properties of AMPH:
These structural characteristics jointly mediate its specific binding to the dopamine transporter (DAT), promoting the release of neurotransmitters.
AMPH is a phenylethylamine compound with multiple neuropharmacological effects. Its main functions include:
| Function | Description |
| Neurotransmitter release | By reversing the direction of action of the dopamine transporter (DAT), it promotes the release of dopamine from the presynaptic membrane. |
| Regulation of synaptic cleft | Inhibit the reuptake of monoamine neurotransmitters and prolong the transmission time of neural signals. |
| Central excitatory effect | Activate the reward pathway (midbrain limbic dopamine system), generating a sense of euphoria and motor excitement. |
| Regulation of cognitive function | Low doses can improve the executive function of patients with attention deficit hyperactivity disorder (ADHD). |
| Metabolic activation | Through the excitatory effect of the sympathetic nerve, it increases the basal metabolic rate and energy expenditure. |
The effect of AMPH shows dose-dependent characteristics: therapeutic doses (5-30mg) can improve attention, while abusive doses (>50mg) lead to overexcitement and addiction. Its pharmacodynamic curve shows a rapidly rising platform-like pattern, which is directly related to the occupancy of dopamine transporters. It is worth noting that the intensity of the effect of AMPH on different monoamine systems (dopamine, norepinephrine, 5-HT) varies significantly, and this selectivity is closely related to its molecular structural characteristics.
1. Amano, Ryota, et al. "Case report: Reversible brain atrophy with low titer anti-amphiphysin antibodies related to gastric adenocarcinoma." Frontiers in Neurology 14 (2023): 1211814. https://doi.org/10.3389/fneur.2023.1211814
This case reports a 75-year-old female who presented with tremors, hallucinations and cognitive impairment. MRI showed rapid progressive brain atrophy. Serum testing confirmed positive anti-AMPH antibody, accompanied by gastric cancer. After immunotherapy and tumor resection, symptoms improved, brain atrophy alleviated, and antibody levels decreased. This case suggests that Western blotting may still be truly positive when TBA is negative.
2. Chen, Yajun, et al. "AMPH1 functions as a tumour suppressor in ovarian cancer via the inactivation of PI3K/AKT pathway." Journal of Cellular and Molecular Medicine 24.13 (2020): 7652-7659. https://doi.org/10.1111/jcmm.15400
This study is the first to confirm that AMPH1 exerts an anti-cancer effect in ovarian cancer, inhibiting cell proliferation, migration and promoting apoptosis by suppressing the PI3K/AKT signaling pathway. Immunohistochemistry showed that the expression of AMPH1 in ovarian cancer tissues was significantly decreased, and both in vivo and in vitro experiments confirmed its anti-tumor effect.
3. Yan, Xinyu, Wenji He, and Sanqiang Pan. "Amphetamine-induced neurite injury in PC12 cells through inhibiting GAP-43 pathway." NeuroToxicology 93 (2022): 103-111.https://doi.org/10.1016/j.neuro.2022.09.004
Studies have found that amphetamine (AMPH) causes neurite damage in PC12 cells by inhibiting the PKCβ1/GAP-43 pathway. AMPH reduces the level of GAP-43 in striatum and inhibits its phosphorylation. The PKC activator PMA can reverse this injury, while the inhibitor enzastuarin aggravates it. The results indicated that the PKCβ1/GAP-43 pathway was the key mechanism of neurotoxicity of AMPH.
4. Bagalkot, Tarique, and Alexander Sorkin. "Amphetamine induces sex-dependent loss of the striatal dopamine transporter in sensitized mice." eneuro 11.1 (2024).https://doi.org/10.1523/ENEURO.0491-23.2023
In this study, through the HA-DAT gene knock-in mouse model, it was found that after repeated amphetamine (Amph) sensitization, the DAT protein in the striata of male mice significantly decreased by 30-60%, accompanied by a reduction in dopamine transport Vmax, and co-localization with the in vivo marker VPS35 increased. Chloroquine and ROCK1/2 inhibitors can block this process, suggesting that RHO-mediated endocytosis and post-endocytosis transport are involved in DAT degradation. This effect shows brain region specificity (significant in the nucleus accumbens) and gender dependence (male sensitivity), providing new insights into the mechanism of drug addiction.
5. Brynte, Christoffer, et al. "Impulsive choice in individuals with comorbid amphetamine use disorder and attention deficit-hyperactivity disorder." BMC psychiatry 23.1 (2023): 537. https://doi.org/10.1186/s12888-023-05034-x
This study compared the impulsive characteristics of ADHD complicated with amphetamine use disorder (ADHD+AMPH), simple ADHD and the healthy control group. The results showed that the ADHD+AMPH group had significantly higher self-assessment scores in motor skills, attention, and unplanned impulsivity, and performed worse in impulse selection tasks such as delayed aversion and reflex impulses, while there was no difference between the simple ADHD group and the healthy control group. It indicates that patients with ADHD+AMPH have specific impulse selection deficiencies and require targeted intervention strategies.
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