Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists

Abstract

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-HT_2AR), 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-HT_2AR agonists and detail the structure-activity investigations leading to the identification of LPH-5 [analogue (S)-11] as a selective 5-HT_2AR agonist with desirable drug-like properties.

Figure 1

Structures of 2C-B (1), two of its previously reported conformationally restricted analogues, TCB-2 (2) and DMCPA (3), and the ligands investigated in this study.

Figure 2

2C-B (1) and its 4-, 5-, and 6-membered constrained analogues.

Figure 3

Functional properties exhibited by 1, 4, 5, and 6 at stable 5-HT_2AR- and 5-HT_2CR-HEK293 cell lines in a Ca²⁺/Fluo-4 assay. Data are given as mean ± standard deviation (S.D.) values and are from representative experiments performed in duplicate out of at least 3 independent experiments, see Tables 1 and S2.

Figure 4

2C-TFM (18), the N-alkylated analogues 19 and 20, and analogues 21–26 with modifications to the 2′ and/or 5′-position substituents.

Figure 5

Functional properties exhibited by 18, (R)-11, and (S)-11 at stable 5-HT_2AR- and 5-HT_2CR-HEK293 cell lines in a Ca²⁺/Fluo-4 assay. Concentration–response relationships for 2C-TFM (18), (R)-11, and (S)-11 at 5-HT_2AR and 5-HT_2CR, and concentration–inhibition relationship for (S)-11 tested in antagonist mode at 5-HT_2CR using 5-HT EC₉₀ as agonist (bottom, right). Data are averaged data given as mean ± SEM values based on at least three independent determinations performed in duplicate, see Table S2.

Figure 6

Overview of the functional properties, membrane permeability, Log P, LE, and LLE of LPH-5.

Figure 7

Perspective drawing of (R)-11 as its (2S,3S)-tartaric acid salt (see Supporting Information for full experimental details on crystallography and structure elucidation). Displacement ellipsoids of the nonhydrogen atoms are shown at the 50% probability level. Hydrogen atoms have been shown as spheres of arbitrary size. Nitrogen atoms are in blue, fluorine atoms green, and oxygen atoms red.