Discovery and Structure–Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5‑HT_2A Receptor Agonists

Classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) are showing promising results in clinical trials for a range of psychiatric indications, including depression, anxiety, and substance abuse disorder. These compounds are characterized by broad pharmacological activity profiles, and while the acute mind-altering effects can be ascribed to their shared agonist activity at the serotonin 2A receptor (5-HT2AR), their apparent persistent therapeutic effects are yet to be decidedly linked to activity at this receptor. We report herein the discovery of 2,5-dimethoxyphenylpiperidines as a novel class of selective 5-HT2AR agonists and detail the structure–activity investigations leading to the identification of LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with desirable drug-like properties

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

Discovery and Structure–Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5‑HT_2A Receptor Agonists

Classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) are showing promising results in clinical trials for a range of psychiatric indications, including depression, anxiety, and substance abuse disorder. These compounds are characterized by broad pharmacological activity profiles, and while the acute mind-altering effects can be ascribed to their shared agonist activity at the serotonin 2A receptor (5-HT2AR), their apparent persistent therapeutic effects are yet to be decidedly linked to activity at this receptor. We report herein the discovery of 2,5-dimethoxyphenylpiperidines as a novel class of selective 5-HT2AR agonists and detail the structure–activity investigations leading to the identification of LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with desirable drug-like properties

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 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

Published conformationally restrained analogs of 1.

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

Crystal Structure of <em>Lymnaea stagnalis</em> AChBP Complexed with the Potent nAChR Antagonist DH<em>β</em>E Suggests a Unique Mode of Antagonism

<div><p>Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that belong to the Cys-loop receptor superfamily. These receptors are allosteric proteins that exist in different conformational states, including resting (closed), activated (open), and desensitized (closed) states. The acetylcholine binding protein (AChBP) is a structural homologue of the extracellular ligand-binding domain of nAChRs. In previous studies, the degree of the C-loop radial extension of AChBP has been assigned to different conformational states of nAChRs. It has been suggested that a closed C-loop is preferred for the active conformation of nAChRs in complex with agonists whereas an open C-loop reflects an antagonist-bound (closed) state. In this work, we have determined the crystal structure of AChBP from the water snail <em>Lymnaea stagnalis</em> (<em>Ls</em>) in complex with dihydro-<em>β</em>-erythroidine (DH<em>β</em>E), which is a potent competitive antagonist of nAChRs. The structure reveals that binding of DH<em>β</em>E to AChBP imposes closure of the C-loop as agonists, but also a shift perpendicular to previously observed C-loop movements. These observations suggest that DH<em>β</em>E may antagonize the receptor via a different mechanism compared to prototypical antagonists and toxins.</p> </div