17 Jan 2014: Isberg V, Paine J, Leth-Petersen S, Kristensen JL, Gloriam DE (2014) Correction: Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors. PLOS ONE 9(1): 10.1371/annotation/c0047d59-f3e8-4923-8883-dcc991c0e61e. https://doi.org/10.1371/annotation/c0047d59-f3e8-4923-8883-dcc991c0e61e View correction
Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9–11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9–11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9–11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.
Citation: Isberg V, Paine J, Leth-Petersen S, Kristensen JL, Gloriam DE (2013) Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors. PLoS ONE 8(11): e78515. https://doi.org/10.1371/journal.pone.0078515
Editor: Paul Taylor, University of Edinburgh, United Kingdom
Received: June 28, 2013; Accepted: September 18, 2013; Published: November 7, 2013
Copyright: © 2013 Isberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: VI and JP were supported by the Lundbeck- and DEG by the Carlsberg Foundations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has key roles in mood, libido, aggression, anxiety, cognition, sleep, appetite and pain and also regulates peripheral functions in the cardiovascular, gastrointestinal, endocrine and pulmonary system.- Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders., – The serotonergic system comprises 12 Class A G protein-coupled receptors and one ligand-gated ion channel that together are divided into 7 pharmacological subfamilies. The 5-HT2 subfamily consists of the three subtypes, serotonin receptors 2A-C (5-HT2A-C). 5-HT2A inhibition by clinical drugs has antipsychotic (e.g., clozapine) and antidepressive (e.g., mianserin) effects. 5-HT2A subtype stimulation by full or partial agonists mediates the hallucinogenic effects of many natural (e.g. psilocybin and mescaline) and synthetic drugs., , 
The 5-HT2A agonist structures generally fall into one of three categories, phenethylamines, tryptamines and ergolines. There is a clinical need for more highly 5-HT2 subtype-selective ligands and the most attention has been given to the phenethylamine class. The phenethylamine ligand 2C-B (1a in Fig. 1) contains the structural features required for hallucinogenic activity; a primary amine separated from the phenyl ring by two carbon atoms, 2- and 5-aromatic methoxy groups, and a hydrophobic 4-substituent. Methylation of the amine α-carbon, as in DOB (1b), DOB-fly (2b) and DOB-butterfly (3b), results in slightly decreased in vitro affinities but increases the strength and duration of the response in vivo – hypothesized to be a consequence of increased metabolic stability resulting in higher exposure.
5-HT2A affinities are given within parenthesis.
Conformationally constrained analogs, primarily 2–4, have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety.– Mutagenesis and ligand structure-activity data suggest that the 2- and 5-oxygen atoms hydrogen bond to serine residues, S3.36159 and S5.43239, respectively.,  Also the ethyl linker has been constrained, exemplified by 5–7, providing information about the bioactive conformation of the amine functionality. Combined 1,2-constraint by cyclization has only been tested with one compound, 8, which exhibits 373-fold lower affinity than the unconstrained reference DOB (1a). Here, we set out to further explore the structure-activity relationships of 1,2-cyclized phenethylamine ligands. The analysis includes the synthesis of three new compounds, 9–11 (Fig. 2), binding affinity measurements, conformational analysis, receptor homology modeling and ligand docking.
Synthes of the 1,2-cyclized phenethylamines 9–11
The synthetic routes of 9-11 are shown in Figures 3-5 and described in detail in Methods S1 (Supporting information). Briefly, 9 was prepared starting from commercially available 2-bromo-4-methoxyphenol, epoxide 12 underwent 5-exo cyclisation to dihydrobenzofuranyl methanol 13 upon treatment with BuLi, as reported by Bradsher. Introduction of the amino group in 14 was accomplished by a Mitsunobu reaction with phthalimide. This was followed by deprotection to give the free amine 15 and finally 4-bromination to yield 9.
Reagents and Conditions: (a) epichlorohydrin, Cs2CO3, MeCN, reflux, 4 h; (b) BuLi, THF, −78°C to r.t., 30 min; (c) phthalimide, PPh3, DEAD, CH2Cl2, r.t., 1 h; (d) N2H4.H2O, EtOH, reflux, 2 h; (e) Br2, AcOH, r.t., 18 h.
Reagents and Conditions: (a) NaBH4, EtOH, r.t., 2 h; (b) Me3SiCN, BF3.Et2O, CH2Cl2, −78°C to r.t.; (c) DIBALH, THF, reflux, 2 h. The 7-bromochroman-4-one 16 was prepared as previously described.
Reagents and Conditions: (a) Ethyl 3-bromobutyrate, Cs2CO3, MeCN, reflux, 2 hrs; (b) polyphosphoric acid, 90°C for 1 h. (c) NaBH4, EtOH, r.t., 2 h; (d) Me3SiCN, BF3.Et2O, CH2Cl2, −78°C to r.t.; (e) DIBALH, THF, reflux, 2 h.
Compounds 10 and 11 could not be prepared in the same manner as 9 because the required 6-exo/7-exo cyclisations onto the corresponding epoxides did not occur. We were thus forced to incorporate the bromine at an earlier stage to circumvent this problem. 10 was prepared as shown in Figure 4. The 7-bromochroman-4-one 16 was prepared as previously described and reduced with sodium borohydride to alcohol 17. Reaction with trimethylsilyl cyanide afforded nitrile 18, which was reduced with diisobutylaluminiumhydride (DIBALH) to the amine in 10.
11 was synthesized as shown in Figure 5. Bromophenol 19 was alkylated using ethyl 3-bromobutyrate and Cs2CO3 in refluxing acetonitrile. Cyclization of the resulting acid 20 via treatment with polyphosphoric acid afforded dihydrobenzoxepinone 21, which in turn gave access to amine 11 following the same protocol utilized in the synthesis of 10: borohydride reduction, cyanation and DIBALH reduction.
Table 1 shows the binding affinities of published (1−8) and new (9−11) 2-oxygen- and/or amine-constrained phenethylamine ligands. The binding affinities of 9−11 against the 5-HT2A-C receptors were determined in competition assays with [3H]-ketanserin, [3H]-LSD and [3H]-mesulergine as radioligands for 5-HT2A, 5-HT2B and 5-HT2C, respectively. 9 and 10 have higher affinities in 5-HT2B-C than 5-HT2A. This was unexpected as the 5-HT2A and 5-HT2C affinities are typically the most similar. The highest affinity, 70 nM, is displayed by 10 in 5-HT2B. 11 is inactive in 5-HT2A and 5-HT2C and displays only weak affinity (1.9 µM) for 5-HT2B.
8, despite the 7-membered ring, appears to have somewhat higher affinity (422 nM) than 9−11. Of note however, 8 was tested in rat 5-HT2A, in which the binding site bears more resemblance to that of 5-HT2B-C as these three receptors contain an alanine in position 5.46 whereas human 5-HT2A holds a more polar serine residue. Thus, until 8 has been tested in human 5-HT2A or 5-HT2B-C we consider it equipotent to 9−10. Also ligands 1b and 3a-b have been tested in rat receptors and may not be equipotent if tested in human receptors.
The 1,2-heterocyclized analogs 8−11 display at best a 480-fold lower affinity at 5-HT2A than the unconstrained reference 2C-B (1a). However, pharmacological testing of 9−11 against all three 5-HT2 subtypes, revealed significantly higher affinities for the 5-HT2B and 5-HT2C receptors. Below we set out to rationalize these two findings by ligand conformational analysis and, for the first time, ligand docking inside the 5-HT2B crystal structure. Specifically, the different sections have investigated ligand-receptor interactions, ligand conformational penalties of binding and the optimal positions of the 2-oxygen and amine functionalities in comparison to the highest affinity reference compounds, 4 and 5, respectively.
The receptor binding site can accommodate 7-membered 1,2-heterocycles
The 5-HT2B receptor has been crystallized in complex with a partial agonist, ergotamine. The reference ligands Bromo-DragonFLY (4) and 2C-TCB (5) could be docked directly into this crystal structure, but a small optimization of the binding pocket was needed to adapt it to the phenyl-ethylamine scaffold. The contacts for the charged amine, phenyl ring and 4-bromo functionalities were all in perfect alignment with the interaction map of the binding site. The triple-ring core of 2C-TCB (5) was better accommodated by tilting F6.52341 slightly towards TMH5 to the same position as observed in the G protein-bound β2 adrenergic structure. The previously described hydrogen bonding between the 2-oxygen functionality and S3.36139 required rotation of the oxygen dihedral towards TMH5 until close (0.6 Å) to the most frequent state (42%) in the library. The proposed hydrogen bond between the 5-oxygen and S5.43222 hydroxyl cannot form as the oxygen atom pair distances are 5.8 and 5.7 Å for Bromo-DragonFLY (4) and 2C-TCB (5), respectively). Inspection of the crystal structure shows that the base (i.e. C-alpha to C-beta bond) of the S5.43222 side chain projects towards TMH6 rather than TMH3 and that F6.52341 blocks access.
Also the 1,2-cyclized compounds 8−11 could be docked directly into the 5-HT2B structure (Figure 6a-d). Similar contacts were achieved for the charged amine and phenyl ring, whereas the 4-bromo pointed deeper and closer to A5.46225. Their 2-oxygen lone pairs are directed in opposite direction compared to the reference ligands and the optimal hydrogen bonding angle was found to be for the third rotameric state of S3.36139 (21% frequency in rotamer library), which positions the hydroxyl deeper and just below the ligands. For compounds 8 and 9 both enantiomers fitted, although (S)-8 and (R)-9 formed more optimal receptor interactions. For 10 and 11 only the R-enantiomer fitted in a way that the 2- and 5-oxygens could be directed towards the corresponding receptor contacts. In conclusion, all compounds could be docked into the 5-HT2B receptor. The 2-oxygen to S3.36139 hydrogen bond could form, but required alternative rotamer shifts. A 5-oxygen to S5.43222 hydrogen bond could not be formed. Arguably, it may form in another conformational receptor state, but it is unlikely that the helical backbones would move enough. If such as bond is formed it could however be indirect being bridged either by a water molecule or the proximal residue N6.55344.
a-d) Docking poses for 8−11 the 5-HT2B crystal structure. 8−11 have similar contacts as the reference compounds 4 and 5 for the charged amine, and phenyl ring, whereas the 4-bromo points deeper and closer to A5.46225. e-h) The docked poses of 8−11 (green carbons) overlaid on their calculated lowest energy conformations (magenta carbons). 11 has a high conformational energy penalty, Epen (21.4 kJ/mol) upon binding, which is consistent with its lack of or low affinity for 5-HT2A-C. i-l) Comparison of the positions of the amine side chains of 8−11 (green carbons) superimposed onto the docked reference 5 (magenta carbons). NH3Dist is the distance (Å) between the amines of 8−11, respectively, and 5. The distance is greatest for 11, indicating a conformationally strained amine side chain upon binding. m-p) Comparison of the lone pair orientations of the 2-oxygens of 8−11 (green carbons) and 4 (magenta carbons). The lone pair vectors (semi-transparent sticks) of 8−11 all differ significantly from 4. All superimpositioning (Fig. 6e-p) was made on the phenyl, bromine, 2-oxygen and 5-oxygen atoms.
The inactive compound 11 exhibits a high conformational penalty of binding
We calculated the conformational energy penalties of binding for 8−11 by comparing the energies of the receptor-bound poses with their respective lowest energy conformation in solution (Fig. 6e-h). The inactive 11 exhibits a considerable penalty, 21.4 kJ/mol, whereas 8−10 display close to none. A closer inspection of 8 and 11, which both have 7-membered rings shows that their ring conformations are exactly the same in the global energy minimum, whereas their amine positions differ by 2.7 Å. In the docking, 11 displays a higher energy ring conformation, which is necessary to direct the amine in the proximity of D3.32 and also has a strained methyl amine linker. As the binding sites of 5-HT2A-C are identical in the region around this ring, this observation provides a plausible explanation also to the lack of affinity of 11 in the 5-HT2A and 5-HT2C receptors.
1,2-cyclization alters the amine and 2-oxygen lone pair orientations and shifts the overall poses
We next investigated the orientation of the amine functionality. Figure 6i-l shows a superimposition of the minimum energy conformations of 8−11 to that of docked (R)-TCB-2 (5), which is the amine-constrained ligand with the highest affinity (5-HT2A: 0.26 nM). In 8 the amine is slightly distanced whereas in 9−11 it is positioned closer towards the side of the interacting D3.32. The distances between the charged nitrogen atoms are 1.3, 1.5, 1.5 and 2.3 Å for 8−11, respectively, from that of 5. After docking, the distances are 0.5−3.2 Å, and the amine is shifted primarily upwards compared to TCB-2 (5). We next turned to the lone pair orientations of the 2-oxygen, which has been suggested based on mutagenesis to form a hydrogen bond with S3.36. Figure 6m-p shows a superimposition of the minimum energy conformations of 8−11 to that of the docked Bromo-DragonFLY (4), which is the 2-oxygen-constrained ligand with the highest affinity (0.02−0.19 nM in 5-HT2A-C). The distances between the 5 and 8−11 2-oxygen atoms are small (0.2 Å in 8,10−11 and 0.5 in 9). However, as expected from their 2D structures, the orientations of the lone pair vectors differ markedly. This has an effect on the docked poses (Fig. 1a-d), in which the 2-oxygen atoms of 8−11 have shifted 1.5−3.0 Å from that of Bromo-DragonFLY (4) away from THM5 and a somewhat higher.
The large changes in the amine orientations of 8−11 seem to be accommodated by the receptor as the interacting residue D3.32 offers a large contact area and there is some flexibility on both sides (one-carbon linkers in the amine and carboxylic acid). Maintaining the 2-oxygen hydrogen bond to S3.36 seems more challenging, as there is less flexibility at this point. Moreover, the amine and 2-oxygen both interact with residues on the same helix, TMH3, and a helical movement would therefore not relieve the combined constraint. The 1,2-cyclization is therefore compensated for by a translation of the ligand that shifts the positions of the methoxy, bromine and phenyl functionalities and, in particular, the 4-bromo and 5-oxygen substituents are located markedly deeper. Taken together, the constrained moieties may to some extent be compensated for by flexible receptor contact points, but alter the position and/or angle of the core scaffold and so modulate the remote 4-bromine and 5-oxygen functionalities.
Differences in the binding site may explain the lower affinity of 8−11 in 5-HT2A and higher affinity of 10−11 in 5-HT2B
9−10 display 5−12 fold higher affinities in 5-HT2B-C than 5-HT2A. Arguably, this difference is too large to only be due to the use of different radioligands; an antagonist for 5-HT2A (ketanserin) and agonists for 5-HT2B (LSD) and 5-HT2C (mesulergine). An additional factor is the difference in the binding sites. As noted above human 5-HT2A holds a polar serine residue in 5.46, whereas 5-HT2B-C have an alanine (Fig. 7d-f). In our ligand docking, the 4-bromo substituent is closer to 5.46 in the 1,2-cyclized compounds 8−11. Thus, it is plausible that the lower affinity of these ligands in 5-HT2A is caused by a less favorable environment for the 4-bromine in the presence of S5.46. In future studies it would therefore be interesting to exchange the 4-bromine for a polar substituent, for example a hydroxyl or nitrile, too see if the affinity profile is inverted (i.e. higher affinity in 5-HT2A than 5-HT2B-C).
The maps were produced with SiteMap. The 5.39 methionine in 5-HT2B (b) reduces the size of hydrophobic pocket. The 2-oxygen matches the hydrogen bond acceptor area for S3.36 interaction whereas the 5-oxygen cannot reach that of S5.43 (left and right sides, respectively, in d-f). 5.46 holds a serine in 5-HT2A (d) resulting in an hydrogen bond acceptor site close to TMH5, where the other receptor subtypes display hydrophobic areas.
5.39, located approximately two helical turns higher on TMH5, is close to the 5-oxygen of the docked phenethylamine ligands. This position is occupied by a methionine in 5-HT2B, but an alanine in 5-HT2A and 5-HT2C (Fig. 7a-c). This could give more room for large ligands in the latter receptors tentatively explaining the somewhat lower affinities of Bromo-DragonFLY (4) and DOB-fly (2b) in 5-HT2B (Table 1). Taken together, the two subtype differences could explain some of the observed affinity profiles, but many ligands have only been tested in 5-HT2A making it difficult to define any general relationships for all constrained phenethylamines. Future ligand design aiming at selectivity, could exploit the subtype differences.
Previously the effect of 1,2-cyclization of phenethylamines had only been explored with one ligand (8) . Here, we have presented three new 1,2-cyclized of phenethylamines and described their synthetic routes giving access to novel derivatives. The 1,2-heterocyclized analogs 8−11 display at best 480-fold lower affinity at 5-HT2A than the unconstrained reference 2C-B (1a, Table 1). The ligand docking results show that all four 1,2-heterocyclized compounds can be accommodated in the binding site, but conformational analysis showed that 11 can only bind in a higher-energy conformation. The amine orientation in 9−11 is shifted significantly to the side of D3.32 as compared to the reference (5), however the docking poses display near optimal interactions. This is because the interacting atoms both have flexible 1-carbon linkers and due to the shift in the scaffold placement. The 2-oxygen lone pairs in 8−11 have opposite directions to that of earlier constrained ligands.– The docked poses of 8−11 still display hydrogen-bonding to S3.36, but this requires a very specific positioning of the 2-oxygen with little flexibility and a slight of the scaffolds. The constraints in 9−11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in human 5-HT2A. Future medicinal chemistry programs should evaluate whether polar 4-substituted analogs can invert the target preferences.
Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.
Ligand docking into the 5-HT2B crystal structure
The 5-HT2B receptor crystal structure in complex with the partial agonist ergotamine (4IB4) was downloaded from the protein data bank and prepared with the Maestro protein preparation workflow. A map of the interaction features and areas of the binding site was generated by SiteMap. Accordingly, as a first step to adapt the binding pocket to phenylethylamine ligands, the hydroxyl hydrogen atoms of S3.36139 and S5.43222 were rotated towards the center of the binding site to constitute hydrogen bond donors. In opposite, the hydroxyl hydrogen of S3.37140 rotated away to enlarge a hydrophobic portion of the binding site. The triple-ring core of 2C-TCB (5) was better accommodated by tilting F6.52341 slightly towards TMH5 to the same position as observed in the G protein-bound β2 adrenergic structure. The binding sites of the 5-HT2 receptor subtypes deviate only in two residue positions: 5.46 (5-HT2A: S, 5-HT2B: A and 5-HT2C: A) and 5.39 (5-HT2A: A, 5-HT2B: M and 5-HT2C: A). Models of the 5-HT2A and 5-HT2C binding sites were simply derived by mutation of these two residues.
Glide was used to generate the receptor grid, in which the S3.36 hydroxyl was allowed to rotate. Glide SP was used for the docking, including sampling of ligand ring conformations and increasing the maximum number of output poses from 1 to 10. In a first docking round, (R)-Bromo-DragonFLY (4), (R)-2C-TCB (5) and 8−11 were docked with no further adjustments. In a second subsequent docking, separate grids were prepared for the reference and 1,2-constrained ligands, after shifting of the S3.36 rotamer to provide optimal fit (see Results). Binding poses were evaluated for placement of all interacting moieties as well as strain on the amine linker. For the reference ligands the top scoring poses proved satisfactory, whereas for 8−11 the selected poses were among the first 2−5 presented.
Conformational penalties for strained ligand poses
The lowest energy (global minimum) conformations of 8−11 were calculated using MacroModel conformational searches with exhaustive settings (maximum iterations: 5000 and convergence threshold 0.01) and applying the OPLS2005 force field (used in all calculations). The energies of the bound conformations (all poses with a docking score within one unit of the highest scoring) were also calculated with MacroModel (current energy) after a mild minimization that restricted the movement of the heavy atoms to 0.3 Å. Finally, the conformational energy penalty of binding was calculated as the energy difference between the bound and global minimum conformations.
Conceived and designed the experiments: VI JP JLK DEG. Performed the experiments: VI JP DEG. Analyzed the data: VI SL-P DEG. Contributed reagents/materials/analysis tools: JLK DEG. Wrote the paper: VI JP SL-P JLK DEG.
- 1. Berger M, Gray JA, Roth BL (2009) The expanded biology of serotonin. Annual Review of Medicine 60: 355–366.
- 2. Ramage AG, Villalon CM (2008) 5-hydroxytryptamine and cardiovascular regulation. Trends in Pharmacological Sciences 29: 472–481.
- 3. Monti JM, Jantos H (2008) The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking. Progress in Brain Research 172: 625–646.
- 4. Gershon MD, Tack J (2007) The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132: 397–414.
- 5. Katzman MA (2009) Current considerations in the treatment of generalized anxiety disorder. CNS Drugs 23: 103–120.
- 6. Gray JA, Roth BL (2007) The pipeline and future of drug development in schizophrenia. Molecular Psychiatry 12: 904–922.
- 7. Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE (2007) Serotonergic drugs : effects on appetite expression and use for the treatment of obesity. Drugs 67: 27–55.
- 8. Goadsby PJ (2007) Serotonin receptor ligands: treatments of acute migraine and cluster headache. Handb Exp Pharmacol: 129−143.
- 9. Moltzen EK, Bang-Andersen B (2006) Serotonin reuptake inhibitors: the corner stone in treatment of depression for half a century--a medicinal chemistry survey. Curr Top Med Chem 6: 1801–1823.
- 10. Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacology, biochemistry, and behavior 71: 533–554.
- 11. Roth BL (2011) Irving Page Lecture: 5-HT(2A) serotonin receptor biology: interacting proteins, kinases and paradoxical regulation. Neuropharmacology 61: 348–354.
- 12. Gonzalez-Maeso J, Sealfon SC (2009) Psychedelics and schizophrenia. Trends in Neurosciences 32: 225–232.
- 13. Nichols DE (2004) Hallucinogens. Pharmacology & therapeutics 101: 131–181.
- 14. Monte AP, Marona-Lewicka D, Parker MA, Wainscott DB, Nelson DL, et al. (1996) Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups. J Med Chem 39: 2953–2961.
- 15. Monte AP, Marona-Lewicka D, Parker MA, Wainscott DB, Nelson DL, et al. (1996) Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups. Journal of Medicinal Chemistry 39: 2953–2961.
- 16. Whiteside MS, Kurrasch-Orbaugh D, Marona-Lewicka D, Nichols DE, Monte A (2002) Substituted hexahydrobenzodipyrans as 5-HT2A/2C receptor probes. Bioorganic and Medicinal Chemistry 10: 3301–3306.
- 17. Parker MA, Marona-Lewicka D, Lucaites VL, Nelson DL, Nichols DE (1998) A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor. Journal of medicinal chemistry 41: 5148–5149.
- 18. Braden MR, Nichols DE (2007) Assessment of the roles of serines 5.43(239) and 5.46(242) for binding and potency of agonist ligands at the human serotonin 5-HT2A receptor. Molecular pharmacology 72: 1200–1209.
- 19. Braden MR (2007) Towards a Biophysical Basis of Hallucinogen Action.
- 20. McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, et al. (2006) 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. Journal of medicinal chemistry 49: 5794–5803.
- 21. Monte AP, Marona-Lewikcka D, Cozzi NV, Nelson DL, Nichols DE (1995) Conformationally restricted tetrahydro-1-benzoxepin analogs of hallucinogenic phenethylamines. Med Chem Res 5.
- 22. Bradsher CK, Reames DC (1978) A new anionic cyclization of the Parham type. Selective ring opening of epoxides. The Journal of Organic Chemistry 43: 3800–3802.
- 23. Selander H, Nilsson JLG (1972) Tritium Exchange in Specifically Labelled Hydroquinone, Dihydrobenzofuranol and Chromanol Derivatives. Acta Chem Scand 26: 2433–2440.
- 24. Wubbels GG, Brown TR, Babcock TA, Johnson KM (2008) The element effect and nucleophilicity in nucleophilic aromatic photosubstitution (SN2Ar*). Local atom effects as mechanistic probes of very fast reactions. J Org Chem 73: 1925–1934.
- 25. Wacker D, Wang C, Katritch V, Han GW, Huang XP, et al.. (2013) Structural Features for Functional Selectivity at Serotonin Receptors. Science.
- 26. Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, et al. (2011) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477: 549–555.
- 27. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, et al. (2000) The Protein Data Bank. Nucleic Acids Res 28: 235–242.
- 28. (2013) Maestro. 9.5 ed. New York, NY: Schrödinger LCC.
- 29. (2012) SiteMap. 2.6 ed. New York, NY: Schrödinger LCC.
- 30. (2012) Glide. 5.8 ed. New York, NY: Schrödinger LCC.
- 31. Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE (2001) Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists. Journal of Medicinal Chemistry 44: 1003–1010.