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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 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] 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] 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]

History

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JRT was developed by Lee E. Dunlap and David E. Olson at Delix Therapeutics and other colleagues.[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 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 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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