Dopamine releasing agent

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Amphetamine, an NDRA and one of the most well-known DRAs. Amphetamine.svg
Amphetamine, an NDRA and one of the most well-known DRAs.
4-Methylaminorex (4-MAR), the cis- isomer being one of the most dopamine-selective NDRAs known. 4-Methyl-Aminorex.svg
4-Methylaminorex (4-MAR), the cis- isomer being one of the most dopamine-selective NDRAs known.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. [1] [2] [3] [4]

Contents

No selective DRAs are currently known. [5] [6] [7] However, non-selective DRAs, including norepinephrine–dopamine releasing agents (NDRAs) like amphetamine and methamphetamine, serotonin–norepinephrine–dopamine releasing agents (SNDRAs) like MDMA and mephedrone, and serotonin–dopamine releasing agents (SDRAs) like 5-chloro-αMT and BK-NM-AMT, are known. [8] [9] [10] [7]

A closely related type of drug is a dopamine reuptake inhibitor (DRI). [11] [12] [13] In contrast to the case of DRAs, many selective DRIs are known. [11] [12] [13] Examples of selective DRIs include amineptine, modafinil, and vanoxerine. [11] [12] [13]

Selectivity

No selective and robust DRAs are currently known. [5] [6] [7] The lack of known selective DRAs is related to the fact that it has proven extremely difficult to separate dopamine transporter (DAT) affinity from norepinephrine transporter (NET) affinity and retain releasing capability at the same time. [6] Despite evaluation of over 350 compounds, it was reported in 2007 that it had been virtually impossible to dissociate norepinephrine and dopamine release. [6] By 2014, still no selective DRAs had been identified, despite approximately 1,400 compounds having been screened. [7] [3] Similarly, while moderately selective norepinephrine releasing agents (NRAs) are known (e.g., ~10- to 20-fold preference or norepinephrine over dopamine release), [8] [9] [14] [15] no highly selective NRAs had been identified. [7] The inability to identify selective DRAs has been attributed to the strong phylogenetic similarities between the DAT and NET. [6] Although no selective DRAs have been identified, selective SDRAs, albeit with concomitant serotonin receptor agonism, were described in 2014. [10] SDRAs without known serotonin receptor agonism, such as BK-NM-AMT, were described by 2019. [16] [17] [18]

Although no selective DRAs are currently known, many non-selective releasing agents of both dopamine and norepinephrine (norepinephrine–dopamine releasing agents or NDRAs) and of serotonin, norepinephrine, and dopamine (serotonin–norepinephrine–dopamine releasing agents or SNDRAs) are known. [8] [9] Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). [8] [9] These drugs are frequently used for recreational purposes and encountered as drugs of abuse. DRAs, including NDRAs and theoretically also selective DRAs, have medical utility in the treatment of attention deficit hyperactivity disorder (ADHD). [19] SDRAs, for instance 5-chloro-αMT, are less common and are not selective for dopamine release, but have also been developed. [10] [20] Tryptamines like 5-chloro-αMT are the only known releaser scaffold that consistently release dopamine more potently than norepinephrine. [16]

Therapeutic applications

Selective DRAs might have different clinical effects in the treatment of attention deficit hyperactivity disorder (ADHD) than the NDRAs like amphetamines and norepinephrine–dopamine reuptake inhibitors (NDRIs) like methylphenidate that are currently used. [19] For example, they might have improved therapeutic selectivity by reducing or eliminating the cardiovascular and sympathomimetic side effects of NDRAs. [21]

Examples of DRAs

Amphetamines like dextroamphetamine and dextromethamphetamine are fairly balanced NDRAs but release norepinephrine about 2- to 3-fold more potently than dopamine. [8] [9] [15] [22] However, other studies found that dextroamphetamine and dextromethamphetamine were roughly equipotent or slightly favored dopamine in terms of norepinephrine versus dopamine release. [1] [23] A number of potentially more well-balanced NDRAs, including levomethcathinone (l-MC), [15] 3-chloroamphetamine (3-CA; PAL-304), [1] [24] 3-chloromethcathinone (3-CMC; clophedrone; PAL-434), [25] and 2-phenylmorpholine (2-PM; PAL-632), [26] are known, and all appear to be roughly equipotent in inducing dopamine versus norepinephrine release. A few NDRAs, including cis-4-methylaminorex (cis-4-MAR), [27] [28] 3-chlorophenmetrazine (3-CPM; PAL-594), [29] [26] and naphthylmetrazine (PAL-704), [26] appear to release dopamine about 2- to 3-fold more potently than norepinephrine, and hence may be among the most dopamine-selective NDRAs known.

Pemoline, which is structurally related to the aminorex drugs, is a stimulant used to treat ADHD which is said to act as a selective DRI and DRA, but it is said to only weakly stimulate dopamine release. [30] [31] [32] There is reportedly some, albeit mixed, in-vitro evidence that the antidepressant and modestly selective DRI amineptine may, in addition to inhibiting the reuptake of dopamine, selectively induce the presynaptic release of dopamine without affecting release of norepinephrine or serotonin. [33] [34] [35] However, amineptine is larger than the known small structural size limit of monoamine releasing agents, [3] suggesting that it may not in fact be a DRA.

Although no definite selective DRAs have been described, one possible exception is 2-fluoromethcathinone (2-FMC). [16] It has an EC50 Tooltip half-maximal effective concentration for dopamine release of 48.7 nM but induces only 85% release of norepinephrine at a concentration of 10 μM. [16] For comparison, the EC50 values of the NDRA methcathinone are 49.9 nM for dopamine release and 22.4 nM for norepinephrine release and it induces 100% release of norepinephrine at a concentration of 10 μM. [16] [1] Hence, compared to methcathinone, 2-FMC appears to be relatively more selective or efficacious for induction of dopamine release over norepinephrine release. [16] [1] In any case, the EC50 of 2-FMC for induction of norepinephrine release does not seem to be available. [16] Moreover, in another instance, the related drug 3-methoxymethcathinone (3-MeOMC) released only 68% norepinephrine at 10 μM, yet an EC50 value of the drug of 111 nM for induction of norepinephrine release was provided in another publication. [36] [37]

Mechanism of action

See also

References

  1. 1 2 3 4 5 Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. OCLC   181862653. OL   18589888W.
  2. ↑ Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC   3666194 . PMID   23539642.
  3. 1 2 3 Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC   4297708 . PMID   25548026. Article history: Received 6 November 2014 [...] A library of approximately 1400 phenethylamine compounds (PAL compounds) has been screened using these protocols.
  4. ↑ Heal DJ, Gosden J, Smith SL (December 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology. 87: 19–40. doi:10.1016/j.neuropharm.2014.06.012. PMID   24953830.
  5. 1 2 Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB (February 2007). "Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys". J Pharmacol Exp Ther. 320 (2): 627–636. doi:10.1124/jpet.106.107383. PMID   17071819. As is commonly true for existing monoamine releasers, the potency of these compounds to release norepinephrine was similar to or higher than potency to release dopamine, and compounds with exclusive selectivity for dopamine or norepinephrine release are not yet available (Rothman et al., 2001). [...] Second, the present study documented optimal effects with releasers selective for dopamine/norepinephrine versus serotonin release; however, the degree to which the dopaminergic and/or noradrenergic effects of these drugs contributes to their profiles of behavioral effects remains to be determined. Releasers with selectivity for dopamine versus both norepinephrine and serotonin would help address this issue.
  6. 1 2 3 4 5 Rothman RB, Blough BE, Baumann MH (January 2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". AAPS J. 9 (1): E1–10. doi:10.1208/aapsj0901001. PMC   2751297 . PMID   17408232. Based in part on the above rationale, we sought to identify and characterize a non-amphetamine transporter substrate that would be a potent releaser of DA and 5-HT without affecting the release of NE. After an extensive evaluation of over 350 compounds, we found it virtually impossible to dissociate NE- and DA-releasing properties, perhaps because of phylogenetic similarities between NET and DAT.
  7. 1 2 3 4 5 Bauer CT (5 July 2014). Determinants of Abuse-Related Effects of Monoamine Releasers in Rats. VCU Scholars Compass (Thesis). doi:10.25772/AN08-SZ65 . Retrieved 24 November 2024. Another potential determinant for increased abuse potential of [monoamine releasers (MARs)] is selectivity for [dopamine (DA)] versus [norepinephrine (NE)]. [...] amphetamine and other abused monoamine releasers have slightly (2 to 3x) higher potency to release NE than DA (Rothman et al., 2001). [...] ephedrine (a 19-fold NE-selective releaser) has been shown to maintain self-administration in monkeys (Anderson et al., 2001) and substitute for amphetamine (Young et al., 1998) and methamphetamine (Bondareva et al., 2002) in drug discrimination studies in rats. [...] This leads to the hypothesis that NE release is another determinant of the abuse-related effects produce by MARs; however, the role of DA vs. NE selectivity has been difficult to investigate further due to a lack of drugs that possess significant selectivity for DA or NE relative to the other catecholamine. [...] Unfortunately, compounds with low potency to release [serotonin (5HT)] and variable potencies to release DA vs. NE do not exist, [...]
  8. 1 2 3 4 5 Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
  9. 1 2 3 4 5 Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961.
  10. 1 2 3 Blough BE, Landavazo A, Partilla JS, et al. (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters. 24 (19): 4754–4758. doi:10.1016/j.bmcl.2014.07.062. PMC   4211607 . PMID   25193229.
  11. 1 2 3 Xue W, Fu T, Zheng G, Tu G, Zhang Y, Yang F, Tao L, Yao L, Zhu F (2020). "Recent Advances and Challenges of the Drugs Acting on Monoamine Transporters". Curr Med Chem. 27 (23): 3830–3876. doi:10.2174/0929867325666181009123218. PMID   30306851.
  12. 1 2 3 Nishino S, Kotorii N (2016). "Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics". Narcolepsy. Cham: Springer International Publishing. pp. 307–329. doi:10.1007/978-3-319-23739-8_22. ISBN   978-3-319-23738-1.
  13. 1 2 3 Huot P, Fox SH, Brotchie JM (2015). "Monoamine reuptake inhibitors in Parkinson's disease". Parkinsons Dis. 2015: 609428. doi: 10.1155/2015/609428 . PMC   4355567 . PMID   25810948.
  14. ↑ Kohut SJ, Jacobs DS, Rothman RB, Partilla JS, Bergman J, Blough BE (December 2017). "Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys". Psychopharmacology (Berl). 234 (23–24): 3455–3465. doi:10.1007/s00213-017-4731-5. PMC   5747253 . PMID   28889212. In the present experiments, two monoamine releasers, [levomethamphetamine (l-MA)] and [D-phenylalaninol (PAL-329)], were shown to produce cocaine-like discriminative-stimulus effects in monkeys, suggesting that they meet the above criteria. One of these compounds, l-MA, also has been shown to serve as a positive reinforcer in rodents (Yokel and Pickens 1973) and monkeys (Winger et al 1994), further confirming the overlap with behavioral effects of cocaine. Both compounds also exhibit an approximately 15-fold greater potency in releasing NE than DA, which may be therapeutically advantageous.
  15. 1 2 3 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707.
  16. 1 2 3 4 5 6 7 Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology (Berl). 236 (3): 915–924. doi:10.1007/s00213-018-5063-9. PMC   6475490 . PMID   30341459.
  17. ↑ US 20240335414,Baggott MJ, Dalziel S,"Specialized combinations for mental disorders or mental enhancement",published 10 October 2024, assigned to Tactogen Inc.
  18. ↑ "Advantageous tryptamine compositions for mental disorders or enhancement". Google Patents. 20 September 2021. Retrieved 11 November 2024.
  19. 1 2 Heal DJ, Smith SL, Findling RL (2012). "ADHD: current and future therapeutics". Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment. Current Topics in Behavioral Neurosciences. Vol. 9. pp. 361–90. doi:10.1007/7854_2011_125. ISBN   978-3-642-24611-1. PMID   21487953. When predicting the likely efficacy and safety of new therapeutic approaches in ADHD, the knowledge gained from existing drugs can be helpful. The pharmacological characteristics of the most effective drugs for treating ADHD, the stimulants, are summarised below and in Table 3: 1. These drugs produce large and rapid increases in the synaptic concentration of catecholamines in the PFC. 2. There is no obvious ceiling on the magnitude of their effect on catecholamine efflux. 3. The most efficacious ADHD drugs also enhance dopaminergic neurotransmission in sub-cortical brain regions. However, some caveats have to be taken into consideration. For example, lack of information in the public domain indicates that drugs that are selective dopamine releasing agents, or noradrenaline reuptake inhibitors with the pharmacological characteristics of methylphenidate, have not been evaluated as potential ADHD therapies. Hence, it is impossible to know whether sub-cortical dopamine efflux is a critical component of maximal efficacy in an ADHD medication, or alternatively, whether a drug with a selective noradrenergic mechanism that is as powerful as methylphenidate or amphetamine could rival the efficacy of the stimulants.{{cite book}}: |journal= ignored (help)
  20. ↑ Banks ML, Bauer CT, Blough BE, et al. (June 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology . 22 (3): 274–284. doi:10.1037/a0036595. PMC   4067459 . PMID   24796848.
  21. ↑ Sotomayor-Zárate R, Jara P, Araos P, Vinet R, Quiroz G, Renard GM, Espinosa P, Hurtado-Guzmán C, Moya PR, Iturriaga-Vásquez P, Gysling K, Reyes-Parada M (May 2014). "Improving amphetamine therapeutic selectivity: N,N-dimethyl-MTA has dopaminergic effects and does not produce aortic contraction". Basic Clin Pharmacol Toxicol. 114 (5): 395–399. doi:10.1111/bcpt.12168. PMID   24314229.
  22. ↑ Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID   11680410. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.
  23. ↑ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC   3306880 . PMID   22169943.
  24. ↑ Blough BE, Landavazo A, Partilla JS, Baumann MH, Decker AM, Page KM, Rothman RB (June 2014). "Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics". ACS Med Chem Lett. 5 (6): 623–627. doi:10.1021/ml500113s. PMC   4060932 . PMID   24944732.
  25. ↑ Kohut SJ, Fivel PA, Blough BE, Rothman RB, Mello NK (October 2013). "Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys". Int J Neuropsychopharmacol. 16 (9): 1985–1998. doi:10.1017/S146114571300059X. PMID   23768644.
  26. 1 2 3 US 20130203752,Blough BE, Rothman R, Landavazo A, Page KM, Decker AM,"Phenylmorpholines and analogues thereof",published 8 August 2013,issued 11 April 2017, assigned to National Institutes of Health, U.S. Department of Health and Human Services
  27. ↑ Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC   6287711 . PMID   30269490.
  28. ↑ Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, Twamley B, Mahony O, O'Brien J, Elliott SP, Archer RP, Patrick J, Singh K, Dempster NM, Cosbey SH (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–695. doi:10.1002/dta.1668. PMC   4128571 . PMID   24841869.
  29. ↑ Namjoshi OA, Decker AM, Landavazo A, Partilla JS, Baumann MH, Rothman RB, Blough BE (2015). "Chemical modifications to alter monoamine releasing activity of phenmetrazine analogs as potential treatments of stimulant addiction". Drug and Alcohol Dependence. 146: e48. doi:10.1016/j.drugalcdep.2014.09.502.
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  32. ↑ "Cylert (Pemoline)" (PDF). FDA. December 2002. Archived (PDF) from the original on 4 March 2016. Retrieved 15 February 2014.
  33. ↑ J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 29–. ISBN   978-0-444-53266-4.
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  36. ↑ Shalabi AR (14 December 2017). "Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters". VCU Scholars Compass. Retrieved 24 November 2024.
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