LA-3Cl-SB

LA-3Cl-SB
Clinical data
Other namesCl-LSB; Lysergic acid N-(3-chloro-sec-butyl)amide; N-[3-Chlorobutan-2-yl]-6-methyl-9,10-didehydroergoline-8β-carboxamide
Drug classSerotonergic psychedelic; Hallucinogen
ATC code
  • None
Identifiers
  • (6aR,9R)-N-[3-Chlorobutan-2-yl]-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide
Chemical and physical data
FormulaC20H24ClN3O
Molar mass357.88 g·mol−1
3D model (JSmol)
  • CC(Cl)C(C)NC(=O)C1CN(C)C2Cc3c[nH]c4cccc(C2=C1)c34
  • InChI=1S/C20H24ClN3O/c1-11(21)12(2)23-20(25)14-7-16-15-5-4-6-17-19(15)13(9-22-17)8-18(16)24(3)10-14/h4-7,9,11-12,14,18,22H,8,10H2,1-3H3,(H,23,25)
  • Key:DYECHXACIVFYSZ-UHFFFAOYSA-N

LA-3Cl-SB, also known as Cl-LSB or as lysergic acid N-(3-chloro-sec-butyl)amide, is a putative serotonergic psychedelic of the lysergamide family related to lysergic acid diethylamide (LSD).[1][2][3] It has two additional chiral centers in the amide region relative to LSD and hence has four possible diastereomers in this area.[1][2][3] The compound is a chlorinated derivative of lysergic acid 2-butyl amide (LSB).[1][2][3]

The four diastereomers of LA-3Cl-SB completely substitute for LSD in rodent drug discrimination tests, suggesting that they would be hallucinogenic in humans.[1][2][3] There was, however, a 22-fold range of difference in potency for the four compounds in the assay.[1][2][3] In terms of ED50Tooltip median effective dose values, the LA-3Cl-SB diastereomers were 155%, 27%, 11%, and 7% of the potency of LSD.[1][2] As such, the most potent diastereomer of LA-3Cl-SB was notably more potent than LSD itself in terms of producing LSD-like effects in animals.[1][2][3]

LA-3Cl-SB and its diastereomers were first described in the scientific literature by Robert Oberlender of the lab of David E. Nichols at Purdue University by 1989.[1][2][3] The most potent diastereomer of LA-3Cl-SB was the first LSD analogue modified at the amide that was found to be more or similarly as potent as LSD in animals or humans, with all others up to that point resulting in dramatic losses of potency.[1][2] These findings suggested that the N,N-diethylamide moiety of LSD isn't necessarily the most optimal configuration in terms of potency.[1][2] The results were also particularly notable in that LA-3Cl-SB is an N-monoalkylamide rather than an N,N-dialkylamide like LSD.[1][2] Subsequent research by the Nichols group led to the development of related compounds like LSB and LSZ (LA-Azetidide).[4][5][6][2][7][8]

See also

References

  1. ^ a b c d e f g h i j k Oberlender RA (May 1989). "Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens". Purdue e-Pubs. Purdue University. [...] It was decided instead to evaluate the chloro compounds, 17, for biological activity. The original goal of the project could still be achieved, since 4 stereoisomers had been prepared. Although these derivatives do not model the diethyl substituent, their evaluation could be expected to indicate whether the amide substituent bound to a stereochemically demanding site at the receptor. The final products, 5 and 17-1, -2, -3, and -4 were converted into their l- tartrate salts and dissolved in saline in appropriate concentrations. Substitution tests were then performed in LSD-trained rats as described in Chapter 1. [...] The four isomers of 17, and the pyrrolidide 5, completely substituted for LSD. However, the potency of the test compounds varied over a 22-fold range. The least potent compound was 17-4 and 17-1 was found to be more potent than LSD itself. [...] Table 3. Potency of lysergic acid amides in LSD-trained rats. [...] It is particularly noteworthy that 17-1 represents the first amide-substituted LSD derivative with potency that surpasses the parent drug. Thus, the molecular determinants of hallucinogenic activity in the amide moiety may not be achieved optimally by the diethyl group. There has previously been no hint that this may be the case. In addition, the finding that relatively large potency differences exist for the four stereoisomers of 17 represents important evidence that the sensitivity of activity to the features of the amide substituent is not merely related to the size or physicochemical properties of this portion of the molecule. Since the four isomers of 17 differ only in the spatial arrangement of identical atoms, amide conformational properties may be of great significance in optimizing interactive forces at the receptor involved in LSD-like actions. [...] Table 15. DD Data: lysergic acid amides in LSD-trained rats. [...]
  2. ^ a b c d e f g h i j k l Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994). "Lysergamides revisited" (PDF). NIDA Research Monograph. 146: 52–73. PMID 8742794. After condensation of the dimethylaziridines with lysergic acid—the amide protonates—the chloride then attacks the aziridine ring, which then opens to yield the chlorobutyl derivatives (Oberlender 1989) as shown in figure 6. [...] The four diastereomers were separated, purified, and tested in DD studies, and the data are summarized in table 3. It was found that one of the diastereomers was about 50 percent more potent than LSD. This was the first indication that something other than the diethyl amide might give high activity. Because this is a DD assay, it can give false positives, but it rarely, if ever, gives false negatives. So it seems probable that these compounds might have LSD-like activity. [...] TABLE 3. Potency of chlorobutyl and pyrrolidyl lysergamides in rats trained to discriminate 0.08 mg/kg of (+)LSD from vehicle
  3. ^ a b c d e f g Nichols DE, Oberlender R, McKenna DJ (1991). "Stereochemical Aspects of Hallucinogenesis". In Watson RR (ed.). Biochemistry and Physiology of Substance Abuse. Vol. 3. Boca Raton, Fla.: CRC Press. pp. 1–39. ISBN 978-0-8493-4463-3. OCLC 26748320.
  4. ^ Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Current Topics in Behavioral Neurosciences. 36: 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524.
  5. ^ Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT 2A agonists" (PDF). Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi:10.1002/wmts.42. ISSN 2190-460X.
  6. ^ Gumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)". British Journal of Pharmacology. doi:10.1111/bph.17361. PMID 39354889.
  7. ^ Monte AP, Marona-Lewicka D, Kanthasamy A, Sanders-Bush E, Nichols DE (March 1995). "Stereoselective LSD-like activity in a series of d-lysergic acid amides of (R)- and (S)-2-aminoalkanes" (PDF). Journal of Medicinal Chemistry. 38 (6): 958–966. doi:10.1021/jm00006a015. PMID 7699712.
  8. ^ Nichols DE, Frescas S, Marona-Lewicka D, Kurrasch-Orbaugh DM (September 2002). "Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD)". Journal of Medicinal Chemistry. 45 (19): 4344–4349. doi:10.1021/jm020153s. PMID 12213075.


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