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2C-B-5-hemiFLY-α6

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2C-B-5-hemiFLY-α6
Clinical data
Other namesBNAP
Drug classSerotonin receptor modulator
ATC code
  • None
Identifiers
  • 8-bromo-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1,8-bc]furan-4-amine
ChemSpider
Chemical and physical data
FormulaC12H14BrNO2
Molar mass284.153 g·mol−1
3D model (JSmol)
  • COc1cc(Br)c2c3c1CC(N)CC3CO2
  • InChI=1S/C12H14BrNO2/c1-15-10-4-9(13)12-11-6(5-16-12)2-7(14)3-8(10)11/h4,6-7H,2-3,5,14H2,1H3
  • Key:CLZKGXPLDDUCQZ-UHFFFAOYSA-N

2C-B-5-hemiFLY-α6, also known as BNAP, is a serotonin receptor modulator of the phenethylamine and FLY families related to the psychedelic drugs 2C-B and DOB.[1][2][3] It is a cyclized phenethylamine with a partial ergoline- or LSD-like chemical structure.[1][2][3] Its tricyclic structure mimics the A, B, and C rings of LSD.[2][1]

Pharmacology

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The more active syn stereoisomer of the drug shows high affinity for the human serotonin 5-HT2A and 5-HT2C receptors with agonist radioligands (Ki = 13–16 nM and 4–6 nM, respectively).[2][1][4][5] These affinities were 20- to 30-fold lower than those of the related drug DOB-FLY.[2][4] The stereoisomer also showed much weaker affinity for the serotonin 5-HT2B receptor with agonist radioligand (Ki = 280 nM) and for the serotonin 5-HT1A receptor (Ki = 960 nM).[4][5] Affinities for rat serotonin receptors and for human serotonin receptors with antagonist radioligands were much lower.[3] A subsequent study showed the more active enantiomer to be a partial agonist of the rat serotonin 5-HT2A receptor (EC50Tooltip half-maximal effective concentration = 2,090 nM; EmaxTooltip maximal efficacy = 63%).[6][5] Neither stereoisomer produced LSD-like effects in rodent drug discrimination tests.[2][1][3] Unexpectedly, the more active stereoisomer showed relatively high affinity for the five muscarinic acetylcholine receptors (Ki = 12–81 nM).[1][4][3]

History

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2C-B-F-hemiFLY-α6 was first described in the scientific literature by 1995.[4][3] The compound resulted in conclusions that phenethylamines and lysergamides do not necessarily interact with the serotonin 5-HT2A receptor in the same manner.[1][2] Following the negative findings, further investigation in this area was discontinued.[2]

Analogues

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Analogue of 2C-B-5-hemiFLY-α6 with the amine modified showed not only high-affinity partial agonism at the serotonin 5-HT2A receptor but also partially substituted for LSD and DOI in rodent drug discrimination tests.[2][5]

See also

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References

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  1. ^ a b c d e f g Trachsel D, Lehmann D, Enzensperger C (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. p. 847. ISBN 978-3-03788-700-4. OCLC 858805226.
  2. ^ a b c d e f g h i Blaazer AR, Smid P, Kruse CG (September 2008). "Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors". ChemMedChem. 3 (9): 1299–1309. doi:10.1002/cmdc.200800133. PMID 18666267. Substituted tetrahydronaphthofurans have recently been synthesized as phenylalkylamine–ergoline composite molecules designed to mimic the A, B and C ring structure of ergolines.[198] Pharmacological evaluation of compound 42 revealed binding affinities at [125I]DOI-labeled cloned human 5-HT2A (Ki= 13.0 nm), and 5-HT2C (Ki=5.96 nm) receptors, which is 20–30-fold less than the affinity of 39 for these sites. Moreover, these compounds lacked LSD-like behavioral effects in a DD model. Based on these results, further work on structural similarities between ergolines and phenylalkylamines has ceased.[198, 199] ] Investigation into the 2-aminoalkyl side chain orientation led to the synthesis of analogue 43, with a nonplanar side chain. The affinity of compound 43 (Ki=2.6 nm), for [125I]DOI-labeled cloned rat 5-HT2A receptors, was close that of DOB (16, Ki= 2.2 nm) and LSD (3, Ki=3.5 nm). In a functional assay measuring IP3 accumulation, compound 43 was shown to be a partial agonist (EC50=120 nm; 33% of 5-HT stimulation), and it displayed partial substitution in LSD and DOI-trained rats.[199] One conclusion is that the side chain of ligand 43 might not possess the optimal dihedral angle for full receptor activation.
  3. ^ a b c d e f Monte AP, Marona-Lewicka D, Lewis MM, Mailman RB, Wainscott DB, Nelson DL, et al. (June 1998). "Substituted naphthofurans as hallucinogenic phenethylamine-ergoline hybrid molecules with unexpected muscarinic antagonist activity". Journal of Medicinal Chemistry. 41 (12): 2134–2145. doi:10.1021/jm980076u. PMID 9622555.
  4. ^ a b c d e Monte AP (August 1995). Structure-activity relationships of hallucinogens: Design, synthesis, and pharmacological evaluation of a series of conformationally restricted phenethylamines (Ph.D. thesis). Purdue University – via ProQuest.
  5. ^ a b c d Chambers JJ, Parrish JC, Jensen NH, Kurrasch-Orbaugh DM, Marona-Lewicka D, Nichols DE (July 2003). "Synthesis and pharmacological characterization of a series of geometrically constrained 5-HT(2A/2C) receptor ligands". Journal of Medicinal Chemistry. 46 (16): 3526–3535. doi:10.1021/jm030064v. PMID 12877591.
  6. ^ Chambers JJ (2002). Use of conformationally-restricted analogues and homology modeling to provide insight into the nature of the 5-HT2A receptor agonist binding site (Thesis). Purdue University. Table 2. Results of radioligand competition binding studies at cloned receptors. [...] Table 3. Results of the IP3 accumulation studies at cloned rat 5-HT2A receptors. [...]
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