Published conformationally restrained analogs of 1.

<p>5-HT_2A affinities are given within parenthesis.</p

Synthesis of 9.

<p>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.</p

Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT₂ Receptors

<div><p>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, <b>9</b>–<b>11</b>, and describe their synthetic routes. Ligand docking in the 5-HT_2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that <b>11</b> 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 <b>9</b>–<b>11</b> resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT_2A subtype, for which <b>9</b>–<b>11</b> 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.</p></div

Synthesis of 10.

<p>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.<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078515#pone.0078515-Selander1" target="_blank">[23]</a></p

Ligand docking and conformational analyses.

<p><b>a-d)</b> Docking poses for <b>8</b>−<b>11</b> the 5-HT_2B crystal structure. <b>8</b>−<b>11</b> have similar contacts as the reference compounds <b>4</b> and <b>5</b> for the charged amine, and phenyl ring, whereas the 4-bromo points deeper and closer to A5.46²²⁵. <b>e-h)</b> The docked poses of <b>8</b>−<b>11</b> (green carbons) overlaid on their calculated lowest energy conformations (magenta carbons). <b>11</b> has a high conformational energy penalty, E_pen (21.4 kJ/mol) upon binding, which is consistent with its lack of or low affinity for 5-HT_2A-C. <b>i-l)</b> Comparison of the positions of the amine side chains of <b>8</b>−<b>11</b> (green carbons) superimposed onto the docked reference <b>5</b> (magenta carbons). NH₃Dist is the distance (Å) between the amines of <b>8</b>−<b>11</b>, respectively, and <b>5</b>. The distance is greatest for <b>11</b>, indicating a conformationally strained amine side chain upon binding. <b>m-p)</b> Comparison of the lone pair orientations of the 2-oxygens of <b>8</b>−<b>11</b> (green carbons) and <b>4</b> (magenta carbons). The lone pair vectors (semi-transparent sticks) of <b>8</b>−<b>11</b> all differ significantly from <b>4</b>. All superimpositioning (Fig. 6e-p) was made on the phenyl, bromine, 2-oxygen and 5-oxygen atoms.</p

Synthesis of 11.

<p>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.</p

The new conformationally constricted analogs reported in this study.

<p>The new conformationally constricted analogs reported in this study.</p

Structure–Activity Relationships and Identification of Optmized CC-Chemokine Receptor CCR1, 5, and 8 Metal-Ion Chelators

Chemokine receptors are involved in trafficking of leukocytes and represent targets for autoimmune conditions, inflammatory diseases, viral infections, and cancer. We recently published CCR1, CCR8, and CCR5 agonists and positive modulators based on a three metal-ion chelator series: 2,2′-bipyridine, 1,10-phenanthroline, and 2,2′;6′,2″-terpyridine. Here, we have performed an in-depth structure–activity relationship study and tested eight new optimized analogs. Using density functional theory calculations we demonstrate that the chelator zinc affinities depend on how electron-donating and -withdrawing substituents modulate the partial charges of chelating nitrogens. The zinc affinity was found to constitute the major factor for receptor potency, although the activity of some chelators deviate suggesting favorable or unfavorable interactions. Hydrophobic and halogen substituents are generally better accommodated in the receptors than polar groups. The new analog brominated terpyridine (<b>29</b>) resulted in the highest chelator potencies observed so far CCR1 (EC₅₀: 0.49 μM) and CCR8 (EC₅₀: 0.28 μM). Furthermore, we identified the first selective CCR5 agonist chelator, meta dithiomethylated bipyridine (<b>23</b>). The structure–activity relationships contribute to small-molecule drug development, and the novel chelators constitute valuable tools for studies of structural mechanisms for chemokine receptor activation

Design, Synthesis, and Pharmacological Characterization of <i>N</i>- and <i>O</i>‑Substituted 5,6,7,8-Tetrahydro‑4<i>H</i>‑isoxazolo[4,5‑<i>d</i>]azepin-3-ol Analogues: Novel 5‑HT_2A/5-HT_2C Receptor Agonists with Pro-Cognitive Properties

The isoxazol-3-one tautomer of the bicyclic isoxazole, 5,6,7,8-tetrahydro-4<i>H</i>-isoxazolo­[4,5-<i>d</i>]­azepin-3-ol (THAZ), has previously been shown to be a weak GABA_A and glycine receptor antagonist. In the present study, the potential in this scaffold has been explored through the synthesis and pharmacological characterization of a series of <i>N</i>- and <i>O</i>-substituted THAZ analogues. The analogues <i>N</i>-Bn-THAZ (<b>3d</b>) and <i>O</i>-Bn-THAZ (<b>4d</b>) were found to be potent agonists of the human 5-HT_2A and 5-HT_2C receptors. Judging from an elaborate pharmacological profiling at numerous other CNS targets, the <b>3d</b> analogue appears to be selective for the two receptors. Administration of <b>3d</b> substantially improved the cognitive performance of mice in a place recognition Y-maze model, an effect fully reversible by coadministration of the selective 5-HT_2C antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most likely mediate their effects through 5-HT_2A and/or 5-HT_2C receptors, the isoxazoles <b>3d</b> and <b>4d</b> constitute interesting leads for further medicinal chemistry development