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Whereas asimilobine is a selective, lower-potency, high-efficacypartial agonist of the serotonin 5-HT2C receptor,[3] 11-methoxyasimilobine is a highly potent and selective full agonist of both the serotonin 5-HT2A and 5-HT2C receptors, with approximately 8-fold preferential activation of the serotonin 5-HT2C receptor over the serotonin 5-HT2A receptor.[1] Its EC50Tooltip half-maximal effective concentration (EmaxTooltip maximal efficacy) values were 18nM (98%) at the serotonin 5-HT2A receptor and 2.3nM (100%) at the serotonin 5-HT2C receptor.[1] The drug is a biased agonist of the serotonin 5-HT2C receptor, favoring Gqsignaling over β-arrestin recruitment by approximately 6.3-fold.[1] It was among the most potent dual serotonin 5-HT2A and 5-HT2C receptor agonists of a large series of assessed noraporphines.[1]
Besides the serotonin 5-HTA and 5-HT2C receptors, the drug also showed weak agonism of the serotonin 5-HT2B receptor, but only at very high concentrations (EC50 = >10,000nM).[1][2] It showed little activity at a selection of other serotonin receptors.[1]
The chemical synthesis of 11-methoxyasimilobine has been described.[1][2] A variety of analogues of the drug with similar activity have also been described.[1][2]
123456789101112Qin W, Zhang B, Wang Q, Jiang G, Cui J, Chen F, etal. (November 2025). "Discovery of New N-H Aporphine Derivatives As Brain-Penetrant Gq-Biased 5-HT2C Receptor Agonists and Dual 5-HT2C/5-HT2A Receptor Agonists". Journal of Medicinal Chemistry. 68 (21): 23300–23323. doi:10.1021/acs.jmedchem.5c02115. PMID41108743. Most of 2,11-disubstituted derivatives (e.g., 16l, 20n) in series II showed potent 5-HT2CR/5-HT2AR dual agonistic activity. [...] Although 16l exhibited 15.5-fold enhancement in 5-HT2CR potency (EC50 = 2.3 nM, Emax = 100%) and retained weak agonistic activity at 5-HT2BR, it also demonstrated potent 5- HT2AR agonistic activity (EC50 = 18 nM, Emax = 98%), rendering it as a 5-HT2CR and 5-HT2AR dual agonist. [...] Moreover, 16k exhibited minimal agonistic activity toward other members of the 5-HT receptor family, including 5-HT1A, 5-HT1B, 5-HT3, 5-HT4A, 5-HT7A (EC50 > 1 μM; Table S1), similar to that of its 11-methoxy analogue 16l, suggesting 5-HT2R subfamily selectivity of 1,2,11-trisubstituted aporphines. [...] The 1,11-dimethoxy-2-hydroxyl and 2- hydroxyl-11-propoxy derivatives, 16l and 20n, were found to exhibit stronger Gq bias with 6.3-fold (EC50: 9.8 vs 62 nM, p < 0.01) and 13.8-fold (EC50: 5.0 vs 69 nM, p < 0.001) increased potency, respectively, in the Gq assay compared to the βarrestin2 assay (Figure 6D,E). These two compounds also showed higher efficacy in the Gq pathway (118% and 108%) relative to their β-arrestin pathway (82% and 87%), as shown in Figure 6G and Table S3. [...] Additionally, 2,11-disubstituted derivatives 20m20t and 1,2,11-trisubstitued derivatives 16l were identified as the most active 5-HT2CR and 5-HT2AR dual agonists with EC50 ranging from 2.3 to 31 nM, and 6.3 to 83 nM, respectively, but showing low 5-HT2B potency, which may have the therapeutic potential for anxiety, obsessive−compulsive, and substance use disorders.
1234567CN 115108986A,Ye N, Shui W, Qin W, Zhang B, Jiang G,"Aporphine derivative and preparation method and application thereof",published 27 September 2022, assigned to Suzhou Universityand Shanghai Tech University
