doi: 10.1021/cn3000668. Epub 2012 Jul 17.
Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands
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- PMID:23336049
- PMCID: PMC3547484
- DOI: 10.1021/cn3000668
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Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands
Jose I Juncosa Jr et al. ACS Chem Neurosci..
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Abstract
Based on the structure of the superpotent 5-HT(2A) agonist 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, which consists of a ring-substituted phenethylamine skeleton modified with an N-benzyl group, we designed and synthesized a small library of constrained analogues to identify the optimal arrangement of the pharmacophoric elements of the ligand. Structures consisted of diversely substituted tetrahydroisoquinolines, piperidines, and one benzazepine. Based on the structure of (S,S)-9b, which showed the highest affinity of the series, we propose an optimal binding conformation. (S,S)-9b also displayed 124-fold selectivity for the 5-HT(2A) over the 5-HT(2C) receptor, making it the most selective 5-HT(2A) receptor agonist ligand currently known.
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Reagents and conditions:(a)Br2, CH3COOH, rt, 3 h, 68%; (b) i. SOCl2, C6H6, reflux, 1 h; ii. 1,2,3,4-tetrahydroisoquinoline,NEt3, CH2Cl2, reflux, 2 h, 75% (cis/trans = 0.72); (c) BH3.THF,THF, 0 °C, 1 h, then rt, 4 h; then 2 M HCl in EtOH, reflux, 15h, 52%; (d) i. (COCl)2, CHCl3, rt, 1 h; ii.N,O-dimethylhydroxylamine hydrochloride,pyridine, rt, 1 h, 87%; (e)tert-butyl 2-methylbenzylcarbamate,s-BuLi, THF, −40 °C, 15 min, then13, THF, −65 °C to rt, 2 h, 38%; (f) i. CF3COOH,CH2Cl2, rt, 30 min; ii. NaBH4, EtOH,rt, 1 h, 75%; (g) Br2, 1:1 CH3COOH/1,4-dioxane,0 °C to rt, 48 h, 51%.
Reagents and conditions:(a)4-bromoisoquinoline, Pd(PPh3)4, Na2CO3, EtOH, C6H6, H2O,reflux, 4 h, 72%; (b) NaBH3CN, HCl, MeOH, rt, 99%; (c)Br2, CH3COOH, rt, 15 h, 58%; (d) 10% Pd/C, PPh3, Na2CO3, DME, H2O, 80 °C,15 h, 78%; (e) H2 (50–70 psi), PtO2,CH3COOH, rt, 6 h, 88%; (f) Br2, 1:1 CH3COOH/1,4-dioxane, 0 °C to rt, 18 h, 62%; (g)o-anisaldehyde, MeOH, 3 Å MS, NaBH3CN, rt, 6 h, 66%(99% BRSM).
Reagents and conditions:(a)s-BuLi, THF, −45 °C, 45 min, then2,5-dimethoxy-β-nitrostyrene,THF, −45 °C to rt, 30 min, 60%; (b) 2 N HCl (aq), THF,reflux, 15 h, 74%; (c) i. Zn, CH3COOH, rt, 48 h; ii. MeOH,reflux, 15 h, 58%; (d) BH3.THF, THF, reflux, 24 h; then2 M HCl in EtOH, reflux, 12 h, 96%; (e) Br2, CH3COOH, rt, 15 h, 71%;
Reagents and conditions:(a)16, Pd(PPh3)4, Na2CO3, PhCH3, H2O, 65 °C, 24h, 48%;(b)o-anisylmagnesium bromide, THF, Ni(acac)2, dppe, rt, 24 h, 77%; (c) Na, EtOH, reflux, 3 h, 38% (30a), 38% (30b); (d) Br2, 1:1 CH3COOH/1,4-dioxane, 0 °C to rt, 18 h, 66% (8a), 87% (8b).
Reagents and conditions:(a)o-anisylmagnesium bromide, THF, Ni(acac)2, dppe,rt, 18 h, 77%; (b)n-BuLi:LiDMAE, PhCH3, −40 °C, 1 h, then 2,5-dimethoxybenzaldehyde, THF, −78°C to rt, 30 min, 46%; (c) H2 (50 psi), 10% Pd/C,HCl (aq), MeOH, rt, 10 days, 72%; (d) H2 (60 psi), PtO2, CH3COOH, rt, 3 h, 85%; (e) Na, EtOH, reflux,3 h, 38% (35a), 49% (35b); (f) Br2, 1:1 CH3COOH/1,4-dioxane, 0 °C to rt, 15 h (9a) or 63 h (9b), 61% (9a), 64%(9b); (g)O-methylmandeloyl chloride,NaOH, H2O, CH2Cl2, rt, 1.5 h, 28%(36a), 28% (36b); (h) LiEt3BH,THF, rt, 3 days (R,R-9b) or 7 days (S,S-9b), 66% (R,R-9b), 63%(S,S-9b).
ORTEP view of compound36a, obtained by X-raycrystallography.
Stereoviews (crossed-eye) of the structure of(S,S)-9b (dark gray)in the proposedbioactive conformation after docking into a homology model of thehuman 5-HT2A serotonin receptor, superimposed on the structureof (S)-6 (light gray). A is the frontview, and B is the top view. The extracellular side of the receptoris toward the top of panel A.
Compounds (R,R) and (S,S)-9b (orange and blue,respectively) in the simulated 5-HT2A receptor bindingsite.
Comparison between the simulated bindingposes of compounds2 (green) and (S,S)-9b (blue) in the binding site of the 5-HT2A receptor.
References
- Fujii Y.; Saitoh Y.; Tanaka H.; Toyooka H. (2000) Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery. Anesth. Analg. 90, 472–475. - PubMed
- Nichols D. E.; Nichols C. D. (2008) Serotonin receptors. Chem. Rev. 108, 1614–1641. - PubMed
- Siegel G. J., and Agranoff B. W. (1999) Basic neurochemistry: molecular, cellular, and medical aspects, 6th ed., p xxi, 1183, Lippincott-Raven Publishers, Philadelphia.
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