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JRT (drug)

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JRT
Above: JRT molecular structure Below: 3D representation of a (+)-JRT molecule
Clinical data
Drug classSerotonin receptor modulator; Serotonin 5-HT2 receptor agonist; Serotonergic psychedelic; Hallucinogen; Psychoplastogen
ATC code
  • None
Identifiers
  • (7S)-N,N-diethyl-6-methyl-6,9-diazatetracyclo[7.6.1.02,7.012,16]hexadeca-1(15),2,10,12(16),13-pentaene-4-carboxamide
PubChem CID
Chemical and physical data
FormulaC20H25N3O
Molar mass323.440 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)C1CN([C@@H]2CN3C=CC4=C3C(=CC=C4)C2=C1)C
  • InChI=1S/C20H25N3O/c1-4-22(5-2)20(24)15-11-17-16-8-6-7-14-9-10-23(19(14)16)13-18(17)21(3)12-15/h6-11,15,18H,4-5,12-13H2,1-3H3/t15?,18-/m1/s1
  • Key:ZYTVEPYZRGXVRK-KPMSDPLLSA-N

JRT is a serotonin receptor modulator and putative serotonergic psychedelic and psychoplastogen related to lysergic acid diethylamide (LSD).[1][2] It is the analogue of LSD in which the embedded tryptamine structure within the ergoline ring system of LSD has been replaced with an isotryptamine structure.[1]

It acts as a non-selective serotonin receptor modulator, including as a partial agonist of the serotonin 5-HT2A receptor and as an agonist or antagonist of various other serotonin receptors.[1][2] The drug has psychedelic-like, psychoplastogenic, antipsychotic-like, antidepressant-like, and pro-cognitive effects in animals, whilst lacking apparent pro-psychotic-like effects.[1][2] It has significant but reduced psychedelic-like effects compared to LSD.[1][2]

JRT was first described in the scientific literature by 2022.[1][2] It was developed by David E. Olson and colleagues in association with Delix Therapeutics.[1][2] The drug is being investigated as a possible treatment for schizophrenia.[1]

Pharmacology

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In contrast to LSD, (+)-JRT is highly selective for a subset of serotonin receptors and does not bind to various dopamine, adrenergic, or histamine receptors.[1] (+)-JRT shows high affinity for the serotonin 5-HT2 receptors, with Ki values ranging from 2.0 to 184 nM.[1] It is a potent partial agonist of the serotonin 5-HT2A and 5-HT2B receptors (EmaxTooltip maximal efficacy = 33–81% and 48–51%, respectively) and a full agonist of the serotonin 5-HT2C receptor (Emax = 89%).[1] The drug is also an agonist of the serotonin 5-HT1A and 5-HT7 receptors, an antagonist of the serotonin 5-HT5A and 5-HT7 receptors, and binds to the serotonin 5-HT6 receptor.[1] It does not have significant affinity for the serotonin 5-HT1B or 5-HT3 receptors, whereas the other serotonin 5-HT1 receptors and the serotonin 5-HT4 receptor were not reported.[1] (+)-JRT is 4.4- to 180-fold less potent than LSD as a serotonin 5-HT2A receptor agonist in vitro (EC50Tooltip half-maximal effective concentration = 0.4–90 nM vs. 0.09–0.5 nM, respectively) and is less efficacious than LSD in activating the receptor (Emax = 33% vs. 44–63%, respectively).[1] (+)-JRT dissociates from the serotonin 5-HT2A receptor approximately 10-fold more quickly than LSD.[1]

(+)-JRT produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents, and hence would be expected to be hallucinogenic in humans.[1] However, the drug shows a reduced HTR compared to LSD, producing less than half the maximal number of head twitches.[1] It can also antagonize the HTR induced by LSD.[1] Hence, (+)-JRT may be less psychedelic than LSD in humans.[1] The drug is similarly potent as LSD in producing the HTR in mice, with the dose producing peak HTR being 0.2 mg/kg in both cases.[1] (+)-JRT does not affect locomotor activity and does not produce any serotonin behavioral syndrome-type effects.[1] It has been found to inhibit dextroamphetamine-induced hyperlocomotion in female but not male mice, does not exacerbate phencyclidine (PCP)-induced hyperlocomotion, does not worsen dizocilpine (MK-801)-induced prepulse inhibition (PPI), and does not induce PPI deficits itself.[1] Some of these findings are in contrast to LSD, and are suggestive that (+)-JRT lacks psychotic-like effects and may have antipsychotic potential.[1] In addition to the preceding findings, (+)-JRT has been reported to increase neuroplasticity and hence to act as a psychoplastogen, to produce antidepressant-like effects, and to promote cognitive flexibility.[1] It was equivalent with LSD in terms of psychoplastogenic effects.[1]

Chemistry

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JRT is the analogue of the lysergamide lysergic acid diethylamide (LSD) in which the embedded tryptamine structure within the ergoline ring system of LSD has been replaced with an isotryptamine structure.[1] Hence, JRT is not an ergoline, lysergamide, or tryptamine itself, but could be considered a cyclized isotryptamine.[1][2] JRT exists as four enantiomers, including (+)-JRT and (–)-JRT, with (+)-JRT being the active enantiomer.[1]

History

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JRT was developed by Lee E. Dunlap, David E. Olson, and other colleagues at Delix Therapeutics and the University of California, Davis.[1][2] It was first described in the scientific literature by 2022.[1][2]

Research

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JRT is being investigated as a possible treatment for schizophrenia.[1][2]

See also

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References

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  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae Tuck JR, Dunlap LE, Khatib YA, Hatzipantelis CJ, Weiser Novak S, Rahn RM, et al. (April 2025). "Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential". Proceedings of the National Academy of Sciences of the United States of America. 122 (16): e2416106122. doi:10.1073/pnas.2416106122. PMID 40228113.
  2. ^ a b c d e f g h i j Dunlap L (2022). "Chapter 5. An Analog of LSD With Antipsychotic Potential". Development of Non-Hallucinogenic Psychoplastogens (PDF) (Ph.D. thesis). University of California, Davis. pp. 105–114.
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