(R)-11-Hydroxy- and (R)-11-Hydroxy-10-methylaporphine: Synthesis, Pharmacology, and Modeling of D2A and 5-HT1A Receptor Interactions

Abstract

(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.

Structure‐Based Identification of Aporphines with Selective 5‐HT2A Receptor‐Binding Activity

“…The results revealed that ( R )‐roemerine also forms H‐bonding and electrostatic interactions with the equivalent residues, Asp116 and Asp102, in the 5‐HT 1A and D 1 receptors, respectively. The latter observation is in agreement with previous docking studies on other aporphines (51). Nevertheless, the distance between the hydrogen atom of the protonated nitrogen atom of the ligand and the carboxylate oxygen atom of the aspartic acid residue was relatively longer for the 5‐HT 1A (1.62 Å) and D1 (1.69 Å) receptors compared to the corresponding distance (1.58 Å) for the 5‐HT 2A receptor.…”

Molecular Design Using the Minireceptor Concept

“…40,41 This minireceptor model agreed well with the previously described homology-based model, 39 the main difference being the use of Ser168 instead of Ser199 to hydrogen bond to the C11-oxygenated ligands. Ser199 is still close enough to interact with 4 but has to be rotated in order to make room for the larger C11 substituents.…”

“…A homology-based model of the 5-HT 1A receptor had been constructed previously, 39,40 according to a strategy first described for modeling the muscarinic m1 receptor. 35 Manual docking of a series of C11-hydroxylated aporphine ligands into this model led to the identification of three key-interactions: 39 (1) a reinforced electrostatic interaction between the protonated nitrogen of the ligands and Asp116 in helix 3, (2) a hydrogen-bond between the C11-hydroxyl and Ser199 (as a donor) in helix 5, and (3) an aromatic edge-to-face interaction between the aromatic A-ring of the aporphines and Phe362 in helix 6. This model was refined by minireceptor optimization (Yak version 3.9) applied to the isolated active site in a stepwise manner using high-affinity ligands 3-5 in order of increasing size.…”

An Efficient Synthesis of Dimemorfan from Dextromethorphan

“…The mixture was subjected to column chromatography to give 5 in overall yield 62% for the three steps from 3. Final reduction to the N-methyl analogue with lithium aluminum hydride, 15 gave amine 6 which was isolated by simple acid-base extraction methods. Upon addition of phosphoric acid, it resulted in the formation of phosphate salts which was recrystallized from tert-butyl methyl ether (MTBE) and methanol to give the dimemorfan phosphate 7 in high purity (99.7% by HPLC).…”