DON shows much lower affinities for the serotonin5-HT2 receptors than other DOx drugs. However, DOCN also showed by far the greatest degree of selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor (22-fold) of any other assessed DOx drug. Applying this strategy (i.e., cyano substitution) to the 25-NB series resulted in the discovery of 25CN-NBOH, one of the most selective serotonin 5-HT2A receptor agonists discovered to date.
1234Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (January 1999). "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 359 (1): 1–6. doi:10.1007/pl00005315. PMID9933142.
12345Seggel MR, Yousif MY, Lyon RA, Titeler M, Roth BL, Suba EA, etal. (March 1990). "A structure-affinity study of the binding of 4-substituted analogues of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors". Journal of Medicinal Chemistry. 33 (3): 1032–1036. doi:10.1021/jm00165a023. PMID2308135.
↑Trachsel D (2003). "Synthesis of Novel (Phenylalkyl)amines for the Investigation of Structure–Activity Relationships, Part 3: 4-Ethynyl-2,5-dimethoxyphenethylamine (=4-Ethynyl-2,5-dimethoxybenzeneethanamine; 2C-YN)". Helvetica Chimica Acta. 86 (8): 2754–2759. doi:10.1002/hlca.200390224. ISSN0018-019X. The Table summarizes some physicochemical data for the ethynyl group compared to other 4-substituents resulting in some of the most-potent 4-substituted 2,5-dimethoxy-α-methylbenzeneethanamines 2a ± d investigated in in vitro and in vivo studies [3j] [6] (compound 2d had considerably lower affinity at 5-HT2A2) sites [4 f] [6] but is used for structural comparison). [...] A Hansch analysis of a series of 4-substituted 2,5-dimethoxyamphetamines [6] gave a significant correlation between 5-HT2A affinity and the hydrophobicity of the 4- substituents. The measured 5-HT2A binding data for compound 2d bearing the 4-CN substituent showed an affinity of approximately two orders of magnitude lower than that of 2a,b [4f] [6]. For the binding affinity at the 5-HT2A receptor, the comparison of the physicochemical data for 4-substituents (Table) suggests that compound 1 should have substantially higher affinity than 4-cyano-2,5-dimethoxyamphetamine (2d; DOCN) or the α-demethyl congener thereof.
12Halberstadt AL (2017). Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens. Current Topics in Behavioral Neurosciences. Vol.32. pp.283–311. doi:10.1007/7854_2016_64. ISBN978-3-319-52442-9. PMID28097528. Similar to other classes of hallucinogens, NBOMes act as 5-HT2C receptor agonists and are relatively nonselective for 5-HT2A vs. 5-HT2C sites [39]. Given their high affinity and efficacy at 5-HT2A receptors, NBOMes have been developed as 5-HT2A agonist radioligands [50] and as PET tracers [51, 52]. Such work has also encouraged development of NBOMes exhibiting selectivity for 5-HT2A receptors compared with 5-HT2C sites. In contrast to other phenylisopropylamines, 2,5-dimethoxy4-cyanoamphetamine (DOCN, Fig. 6) exhibits moderate (22-fold) selectivity for human 5-HT2A (Ki = 45.7 nM) vs. 5-HT2C (Ki = 1,011 nM) sites labeled with [125I]DOI [46], indicating that 4-cyano substitution represents a potential strategy to augment 5-HT2A selectivity. Applying this strategy to the NBOMe class led to the discovery of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenethylamine (25CN-NBOH), which is reportedly 100-fold selective for 5-HT2A receptors (Ki = 1.3 nM vs. [3H]ketanserin) compared with 5-HT2C receptors (Ki = 132 nM vs. [3H]mesulergine) [25]. However, according to a more recent investigation using the same antagonist radioligands, 25CN-NBOH is only 23-fold selective for 5-HT2A receptors (Ki = 2.2 nM) relative to 5-HT2C sites (Ki = 49.8 nM) [38]. Although the selectivity of 25CN-NBOH may be less than was initially believed, it still exhibits moderate 5-HT2A selectivity. [...] Fig. 6 Structures of the 4-cyano-substituted phenylalkylamines DOCN and 25CN-NBOH [...]
↑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. PMID18666267. A near unity slope was found for 5-HT2A and 5-HT2C receptor affinity correlations, revealing a close correspondence. The only exception was the 4-cyano analogue 24 (DOCN), with a 22-fold higher affinity for 5-HT2A (Ki=45.7 nm) over 5-HT2C (Ki=1011 nm).[63]
↑Jensen AA, Halberstadt AL, Märcher-Rørsted E, Odland AU, Chatha M, Speth N, etal. (July 2020). "The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH". Biochemical Pharmacology. 177 113979. doi:10.1016/j.bcp.2020.113979. PMID32298690.
