Potential Modes of Interaction of 9-Aminomethyl-9,10-dihydroanthracene (AMDA) Derivatives with the 5-HT_2A Receptor: A Ligand Structure-Affinity Relationship, Receptor Mutagenesis and Receptor Modeling Investigation

Abstract

The effects of 3-position substitution of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on 5-HT2A receptor affinity were determined and compared to a parallel series of DOB-like 1-(2,5-dimethoxyphenyl)-2-aminopropanes substituted at the 4-position. The results were interpreted within the context of 5-HT2A receptor models that suggest that members of the DOB-like series can bind to the receptor in two distinct modes that correlate with the compounds’ functional activity. Automated ligand docking and molecular dynamics suggest that all of the AMDA derivatives, the parent of which is a 5-HT2A antagonist, bind in a fashion analogous to that for the sterically demanding antagonist DOB-like compounds. The failure of the F3406.52L mutation to adversely affect the affinity of AMDA and the 3-bromo derivative is consistent with the proposed modes of orientation. Evaluation of ligand-receptor complex models suggest that a valine/threonine exchange between the 5-HT2A and D2 receptors may be the origin of selectivity for AMDA and two substituted derivatives.

Discovery of novel potent and selective ligands for 5-HT2A receptor with quinazoline scaffold

“…NH group in aniline and the hydroxyl group in ethanol moiety of 5a form hydrogen bond interactions with N7.36 and S3.36, respectively. Our predicted binding mode is quite consistent with available site-directed mutagenesis studies which have proved that D3.32 10-12 , Ser3.36 10,13,14 , and Y7.43 [14][15][16][17] are important to binding affinities of 5-HT 2A ligands. It indicates that the piperazinyl-ethanol arm is critical to the activity, as these indispensable interactions determined the binding orientation of the arm down into the hydrophilic binding pocket (ArmBP) enclosed by D3.32, S3.36 and Y7.43, and the tail up to a hydrophobic binding pocket (TailBP) comprised of the extracellular segments of TM-II and VII.…”

“…To rationalize the design of the derivatives, the structural model of the complex 5a-5-HT 2A was constructed by combining molecular docking and all available experimental data ( Figure 2). 5a is lying at the antagonistic crevice comprised of TM-III, TM-VI and TM-VII 10 . And several important interactions were identified.…”

Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors

“…33,34 Subsequent bromination of the alcohol under Appel conditions and displacement of the bromide with KCN resulted in benzonitrile intermediates 77 35 and 78 in good yield. BH 3 -THF reduction 36 and protection with Boc 2 O afforded 79 and 80 .…”

Synthesis and biological evaluation of (phenylpiperazinyl-propyl)arylsulfonamides as selective 5-HT2A receptor antagonists

“…8 Piperazine amides and sulfonamides, such as EMD-281014 (5) 9 and 6, show high affinity as 5-HT 2A antagonists. [10][11][12] Several pharmacophore models for 5-HT 2A receptors have been proposed based on the structure-activity relationships of known antagonists. Typically, the essential geometric characteristics are described by the distances between two aromatic rings (4.6-7.3 Å) and the distances between each aromatic ring and the basic amine nitrogen (5.2-8.4 Å and 5.7-8.5 Å).…”

“…N-(Cyclopropylmethyl)-3-(4-(4-fluorophenyl)piperazin-1-yl)propan-1-amine (10d). Yellow oil (71%): 1 H (CDCl 3 , 400 MHz) d 6.99-6.95 (m, 2H), 6.89-6.86 (m, 2H), 3.16 (t, J = 4.8 Hz, 4H), 2.79 (s, 4H), 2.74-2.68 (m, 4H), 2.62 (t, J = 4.8 Hz, 2H), 2.09-2.07 (m, 2H), 0.88 (s, 1H), 0.66 (q, J = 7.2 Hz, 2H), 0.32 (q, J = 5.2 Hz, 2H).5.2.4.General procedure for the preparation of N-(R 2 -methyl)-4-methoxy-N-(3-(4-(R 1 -phenyl)piperazin-1-yl)propyl)-Ar-sulfonamide(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) For the further conversion to sulfonamides, sodium hydride (1 mmol, 2 equiv) was added to a suspension of N-(R 2 -methyl)-3-(4-(R 1 -phenyl)piperazin-1-yl)propan-1-amine 9 and 10 (0.5 mmol, 1 equiv) in DMF (5 mL). After stirring at 60°C for 30 min under nitrogen, Ar-sulfonylchloride (0.75 mmol, 1.5 equiv) in DMF (5 mL) was added.…”