Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands - PubMed (original) (raw)

. 2013 Jan 16;4(1):96-109.

doi: 10.1021/cn3000668. Epub 2012 Jul 17.

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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. 2013.

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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Figures

Scheme 1

Scheme 1

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, 15 h, 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, then 13, 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%.

Scheme 2

Scheme 2

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).

Scheme 3

Scheme 3

Reagents and conditions: (a) _s_-BuLi, THF, −45 °C, 45 min, then 2,5-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; then 2 M HCl in EtOH, reflux, 12 h, 96%; (e) Br2, CH3COOH, rt, 15 h, 71%;

Scheme 4

Scheme 4

Reagents and conditions: (a) 16, Pd(PPh3)4, Na2CO3, PhCH3, H2O, 65 °C, 24 h, 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).

Scheme 5

Scheme 5

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).

Figure 1

Figure 1

ORTEP view of compound 36a, obtained by X-ray crystallography.

Figure 2

Figure 2

Stereoviews (crossed-eye) of the structure of (S,S)-9b (dark gray) in the proposed bioactive conformation after docking into a homology model of the human 5-HT2A serotonin receptor, superimposed on the structure of (S)-6 (light gray). A is the front view, and B is the top view. The extracellular side of the receptor is toward the top of panel A.

Figure 3

Figure 3

Compounds (R,R) and (S,S)-9b (orange and blue, respectively) in the simulated 5-HT2A receptor binding site.

Figure 4

Figure 4

Comparison between the simulated binding poses of compounds 2 (green) and (S,S)-9b (blue) in the binding site of the 5-HT2A receptor.

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