Para-Bromomethamphetamine

para-Bromomethamphetamine (PBMA; developmental code name V-111), also known as 4-bromomethamphetamine (4-BMA), is a monoaminergic drug of the amphetamine family related to para-chloroamphetamine (PCA; 4-chloroamphetamine).^[1][2][3][4] It was studied by József Knoll and colleagues in the 1970s and 1980s.^[1][3][5]

para-Bromomethamphetamine

Clinical data
Other names	PBMA; 4-Bromomethamphetamine; 4-BMA; p-Bromomethamphetamine; p-BMA; V-111; 4-Bromo-N-methylamphetamine; 4-Bromo-N-methylphenylisopropylamine
Identifiers
IUPAC name 1-(4-bromophenyl)-N-methylpropan-2-amine
CAS Number	4302-85-6
PubChem CID	107257
ChemSpider	96526
Chemical and physical data
Formula	C10H14BrN
Molar mass	228.133 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(CC1=CC=C(C=C1)Br)NC
InChI InChI=1S/C10H14BrN/c1-8(12-2)7-9-3-5-10(11)6-4-9/h3-6,8,12H,7H2,1-2H3 Key:RHHFGACRACGCQS-UHFFFAOYSA-N

Originally thought to selectively act on serotonin, PBMA was subsequently found to act not only on serotonin but also on norepinephrine and dopamine similarly to PCA.^[4][6][7] It has been reported to produce pharmacological effects that have been said to be "somewhat similar" or "indistinguishable" to those of lysergic acid diethylamide (LSD) and various other hallucinogens in various animal species.^[1][7][4][3] However, when the drug was subsequently tested in humans, it showed no hallucinogenic effects whatsoever.^[1] This is analogous to the case of PCA, which can produce the head-twitch response in rodents but is not hallucinogenic in humans.^{[8][9][10][11][1][12]} The hallucinogen-like effects of PBMA in animals can be reversed by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA), suggesting that they are due to elevation of serotonin levels rather than direct serotonin receptor agonism.^[13] Other animal studies have found PBMA to produce stimulant, appetite suppressant, pro-cognitive-like, anticonvulsant, and sleep-disrupting effects.^{[7][14][15][4][16]} Besides its effects, the pharmacokinetics and metabolism of PBMA have been studied in rodents.^[17][5]

PBMA produces serotonergic neurotoxicity of a similar magnitude to PCA and para-bromoamphetamine (PBA) in rodents.^[2][4] Conversely, para-fluoroamphetamine (PFA; 4-fluoroamphetamine) is much less effective.^[2][1]

See also

• 4-Bromomethcathinone
• 4-Fluoromethamphetamine
• para-Chloromethamphetamine
• para-Iodoamphetamine
• 2,5-Dimethoxy-4-bromoamphetamine

References

1. Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN 978-1-4757-0512-6. 3.5.3. 4-Bromo-N-methylphenylisopropylamine: The bromo-counterparts of the chlorophenylisopropylamine have been studied, but have not found extensive clinical evaluation. The primary amine 4-bromophenylisopropylamine (4-bromoamphetamine) is, like the 4-chloro-analog 4-CA (79), a long-term depleter of serotonin in the brain (Fuller et al. (1975). The 4-fluoro analog, while still effective biochemically, is not of as long a duration of action. The N-methyl homolog of 4-bromo-phenylisopropylamine has demanded interest from a separate point of view, however. This compound, 4-bromo-N-methylphenylisopropylamine (81, V-111, p-bromomethamphetamine), has been found to give pharmacological profiles in a large number of animal species, which are indistinguishable from those shown by LSD and other psychotomimetics (Knoll et al., 1970). Although much of the literature appearing over the period from 1965 to 1975 refers to (81) as a psychotomimetic, it had apparently never been clinically assayed in man. It is now known that the compound "has no psychotomimetic effect whatsoever in humans" (Knoll, 1974, personal communication). The high pharmacological potency of (V-111) in the biochemistry of serotonin and its apparent enhancement of learning and memory in experimental animals have maintained an active interest in it in the research area.
2. Fuller RW (June 1978). "Structure-activity relationships among the halogenated amphetamines". Ann N Y Acad Sci. 305 (1): 147–159. Bibcode:1978NYASA.305..147F. doi:10.1111/j.1749-6632.1978.tb31518.x. PMID 152079.
3. Knoll J, Vizi ES, Knoll B (1970). "Pharmacological studies on para-bromo-methamphetamine (V-111) and LSD". Acta Physiol Acad Sci Hung. 37 (1): 151–170. PMID 5433553.
4. Georgiev VP, Petkova BP (December 1976). "The effect of p-bromomethamphetamine (V-111), a selective serotoninergic amphetamine, on the convulsive seizure excitability threshold in mice". Neuropharmacology. 15 (12): 763–766. doi:10.1016/0028-3908(76)90005-8. PMID 138097.
5. Szökó E, Kalász H, György A, Knoll J, Magyar K (1989). "[Metabolism of para-bromomethamphetamine in the rat]". Acta Pharm Hung (in Hungarian). 59 Suppl 1: 63–68. PMID 2641637.
6. Tekes K, Magyar K, Knoll J. The effect of para-substituted amphetamines on the synaptosomal uptake of [3H]-dopamine. Fifth Congress of the Polish Pharmacological Society, Szczecin. p. 21.
7. Brawley P, Duffield JC (March 1972). "The pharmacology of hallucinogens". Pharmacol Rev. 24 (1): 31–66. PMID 4626282.
8. Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". In Halberstadt AL, Vollenweider FX, Nichols DE (eds.). Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 159–199. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. PMC 5787039. PMID 28224459. Amphetamine and methamphetamine, which act primarily by increasing carrier-mediated release of dopamine and norepinephrine, do not provoke head twitches (Corne and Pickering 1967; Silva and Calil 1975; Yamamoto and Ueki 1975; Jacobs et al. 1976; Bedard and Pycock 1977; Halberstadt and Geyer 2013). By contrast, the 5-HT releasing drugs fenfluramine and p-chloroamphetamine (PCA) do produce a robust HTR (Singleton and Marsden 1981; Darmani 1998a). Fenfluramine and PCA are thought to act indirectly, by increasing carrier-mediated release of 5-HT, because the response can be blocked by inhibition of the 5-HT transporter (Balsara et al. 1986; Darmani 1998a) or by depletion of 5-HT (Singleton and Marsden 1981; Balsara et al. 1986). [...] Because indirect 5-HT agonists such as fenfluramine, PCA, and 5-HTP are not hallucinogenic (Van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), their effects on HTR can potentially be classified as false-positive responses.
9. Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD (May 2020). "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology. 167: 107933. doi:10.1016/j.neuropharm.2019.107933. PMC 9191653. PMID 31917152. Indirect 5-HT2A agonists such as fenfluramine, p-chloroamphetamine (PCA), and 5-hydroxytryptophan (5-HTP) induce head twitches in rodents (Corne et al. 1963; Singleton and Marsden 1981; Darmani 1998) but do not act as hallucinogens in humans (van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), However, overdoses of compounds that increase serotonin (5-HT) release can result in 5-HT syndrome, which sometimes includes hallucinations (Birmes et al. 2003; Evans and Sebastian 2007).
10. Orikasa S, Sloley BD (1988). "Effects of 5,7-dihydroxytryptamine and 6-hydroxydopamine on head-twitch response induced by serotonin, p-chloroamphetamine, and tryptamine in mice". Psychopharmacology (Berl). 95 (1): 124–131. doi:10.1007/BF00212780. PMID 3133691. Head-twitch response (HTR) in mice was induced by intracerebroventricular injection of tryptamine (TRA) as well as serotonin (5-HT) and p-chloroamphetamine (PCA). Pretreatment with 5,7-dihydroxytryptamine enhanced both the 5-HT-induced and the TRA-induced HTR. The PCA-induced HTR, however, was attenuated by the drug. On the other hand, pretreatment with 6-hydroxydopamine did not alter the 5-HT response but enhanced both the PCA- and the TRA-induced response. These results suggest that 5-HT may directly stimulate the post-synaptic receptors, while the PCA response may be based on the release of endogenous 5-HT.
11. Wojtas A, Gołembiowska K (December 2023). "Molecular and Medical Aspects of Psychedelics". Int J Mol Sci. 25 (1): 241. doi:10.3390/ijms25010241. PMC 10778977. PMID 38203411. While some false positives have been identified, such as fenfluramine, p-chloroamphetamine, and 5-hydroxytryptophan, the test predominantly exhibits specificity for 5-HT2A receptor agonists [15].
12. Fuller RW (May 1992). "Effects of p-chloroamphetamine on brain serotonin neurons". Neurochem Res. 17 (5): 449–456. doi:10.1007/BF00969891. PMID 1528354.
13. Azzaro AJ, Rutledge CO (November 1973). "Selectivity of release of norepinephrine, dopamine and 5-hydroxytryptamine by amphetamine in various regions of rat brain". Biochem Pharmacol. 22 (22): 2801–2813. doi:10.1016/0006-2952(73)90147-0. PMID 4761552. The role of 5-HT in mediating the behavioral effects of amphetamine is also not entirely clear. Knoll37 suggested that the psychotomimetic effects obtained with high doses of amphetamine are related to 5-HT metabolism. He observed that the psychotomimetic effects of p-bromomethamphetamine are antagonized by pretreatment with p-chlorophenylalanine, a substance which depletes 5-HT by inhibition of its synthesis. This suggests that 5-HT is necessary to obtain the psychotomimetic effects of amphetamine and data from this study indicate that high concentrations of amphetamine release 5-HT from brain tissue containing 5-HT neurons.
14. Knoll J, Knoll B (1975). "p-Bromo-methamphetamine (V-III) induced improvement of learning ability in rats". Int J Neurol. 10 (1–4): 198–221. PMID 1181310.
15. Knoll J (September 1979). "Satietin: a highly potent anorexogenic substance in human serum". Physiol Behav. 23 (3): 497–502. doi:10.1016/0031-9384(79)90049-0. PMID 116263.
16. Juvancz P (April 1981). "The effect of p-bromomethamphetamine (V-111) on sleep on the rat". Eur J Pharmacol. 70 (4): 461–466. doi:10.1016/0014-2999(81)90357-5. PMID 7238572.
17. Magyar K, Tekes K, Zólyomi G, Szüts T, Knoll J (1981). "The fate of p-bromo-methylamphetamine (V-111) in the body". Acta Physiol Acad Sci Hung. 57 (3): 285–307. PMID 7304194.