LA-Aziridine
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| Other names | LSD-Aziridine; N-(2,3-Dimethylaziridin-1-yl)lysergamide; Lysergic acid-(2,3-dimethylaziridinyl)amide |
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| Formula | C20H23N3O |
| Molar mass | 321.424 g·mol−1 |
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LA-Aziridine, also known as N-(2,3-dimethylaziridin-1-yl)lysergamide or as lysergic acid-(2,3-dimethylaziridinyl)amide, is a chemical compound of the lysergamide family related to lysergic acid diethylamide (LSD).[1][2][3][4] It is an analogue of LSD in which the N,N-diethyl groups have been fused together to form an N-(2,3-dimethylaziridine) ring moiety.[1][3][4] The compound has two additional chiral centers in the aziridine region and thus has three diastereomeric forms: (R,R)-trans, (S,S)-trans, and cis.[4] LA-Aziridine is closely related to lysergic acid 2,4-dimethylazetidide (LA-Az, LSZ, or LA-Azetidide).[2]
The laboratory of David E. Nichols and colleagues synthesized LA-Aziridine in the 1980s while studying the influence of stereoselectivity on lysergamide activity.[1][2][4] However, LA-Aziridine proved to be chemically unstable such that in-vivo usefulness was precluded, and they abandoned their efforts with the compound.[1][2][4] Instead, the group studied LA-3Cl-SB, another analogue of LSD in which the diethylamide moiety was replaced with a 2-chloro-1-methylpropylamide moiety and that had four possible stereoisomers.[1][4] These stereoisomers successfully substituted for LSD in rodent drug discrimination tests with varying potencies.[1][4] In addition, Nichols and colleagues subsequently turned their attention to LSZ, which proved active and did not have the stability problems of LA-Aziridine.[2][5]
Other analogues besides LA-Aziridine and LSZ have also been studied, for instance the N-(2,5-dimethylpyrrolidide) (a derivative of LA-Pyr) and the N-(2,6-dimethylpiperidide) (a derivative of LA-Pip) analogues.[6][7]
See also
[edit]References
[edit]- ^ a b c d e f Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994). "Lysergamides revisited" (PDF). NIDA Research Monograph. 146: 52–73. PMID 8742794.
- ^ a b c d e 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.
Our earliest efforts focused on lysergamides prepared from 2,3-dimethylaziridines, a strategy that would introduce essentially no additional bulk into the amide moiety. Those attempts were abandoned, however, with the discovery of the extreme chemical lability of N-acyl aziridines. Condensation of lysergic acid with either cis- or trans-2,3-dimethylaziridine, using a variety of very mild methods, led only to isolation of aziridine ring-opened products.1 This paper describes the synthesis and pharmacological evaluation of three lysergic acid amides prepared from cis (meso)-, trans-(2R,4R)-, and trans-(2S,4S)-2,4- dimethylazetidines 2a-c, respectively. Not only did those products prove to be suitably stable but also the azetidine ring is less strained and clearly gives a more appropriate model of a dialkylamide than does an aziridine. The use of dialkylazetidines as constrained amines has been previously recognized.8
- ^ a b Nichols DE, Monte A, Huang X, Marona-Lewicka D (1996). "Stereoselective pharmacological effects of lysergic acid amides possessing chirality in the amide substituent" (PDF). Behavioural Brain Research. 73 (1–2): 117–119. doi:10.1016/0166-4328(96)00080-0. PMID 8788487.
Several years ago, we attempted to constrain the diethyl groups of LSD by incorporating them into a 2,3-dimethylaziridine moiety (Fig. 1 ). However, the lysergoyl aziridines proved extremely labile to acid, and in the presence of protons and chloride ion the acylated cis- and trans-dimethylaziridine rings were cleaved to afford 4 isomeric 2-chlorobutyllysergamides [7]. Although we never firmly established the absolute configurations of these 4 isomers, the ED50 values for substitution in the drug discrimination assay are shown in Fig. 1, and they varied widely. Thus, these data showed, for the first time, that the introduction of chirality into the amide groups would lead to differing biological activities. We therefore undertook to study the effects of chiral alkyl groups on LSD-like biological activity. [...] Fig. 1. HCl-catalyzed cleavage of lysergoyl cis- and trans-dimethylaziridines gave 4 isomeric chlorobutylamides with differing LSD-like in vivo activity in the drug discrimination assay [7].
- ^ a b c d e f g Oberlender RA (May 1989). "Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens". Purdue e-Pubs. Purdue University.
As the high reactivity of N-acylaziridines became increasingly apparent, concern increased regarding the successful completion of the project with the original target molecules. The necessity of acidifying the lysergamides, in order to prepare water soluble salts suitable for pharmacology studies, may present a significant hazard to the integrity of the aziridine ring. Even if the compounds remained intact long enough to be injected into rats, it seemed likely that a ring-opening attack by biological nucleophiles would occur at physiological pH before the compounds could accumulate in the brain. Therefore, the high reactivity of N-acyl aziridines that is useful synthetically (Pettit, et al., 1967), may create significant problems regarding their in vivo use. 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.
- ^ Nichols DE (October 2018). "Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)" (PDF). ACS Chemical Neuroscience. 9 (10): 2331–2343. doi:10.1021/acschemneuro.8b00043. PMID 29461039.
- ^ Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524.
Table 1 5-HT2A 5-HT2C, and 5-HT1A receptor affinity and functional effects for selected lysergamides [...]
- ^ Parrish JC (30 October 2007). Toward a molecular understanding of hallucinogen action (Ph.D. thesis). Purdue University – via Purdue e-Pubs.