RESUMEN
The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to substantially larger N-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C-B were prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, -2-, or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually favored affinity for all three 5-HT2 receptor subtypes with compound 5 exhibiting 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HT2AR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HT2C subtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HT2A than the 5-HT2C receptor, interacting with the Trp3366.48 toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gq protein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype.
Asunto(s)
Alucinógenos , Serotonina , Agonistas del Receptor de Serotonina 5-HT2 , Receptor de Serotonina 5-HT2A , Simulación del Acoplamiento Molecular , Fenetilaminas , Nitrógeno , Receptor de Serotonina 5-HT2CRESUMEN
The human 5-HT2 receptor subtypes have high sequence identity in their orthosteric ligand-binding domain, and many agonists are poorly selective between the 5-HT2A and 5-HT2C subtypes. Nevertheless, their activation is associated with different pharmacological outcomes. We synthesized five phenethylamine analogs in which the benzene ring is replaced by a bulky dibenzo[b,d]furan moiety and found a couple with >70-fold 5-HT2C selectivity. Molecular docking studies of the most potent compound (5) at both receptor subtypes revealed the likely structural basis of its selectivity. Although in both cases, some crucial interactions are conserved, the change of the Ala2225.46 residue in the 5-HT2C receptor to the larger Ser2425.46 in the 5-HT2A subtype, which is the only structural difference between the orthosteric binding pockets of both receptors, weakens a π-π stacking interaction between the dibenzofuran moiety and the important Phe6.52 residue and breaks a hydrogen bond between the dibenzofuran oxygen and Ser5.43, explaining the selectivity of compound 5 for the 5-HT2C receptor. We believe that this effect of the residue at position 5.46 merits further exploration in the search for selective 5-HT2C receptor agonists that are of considerable interest in the treatment of schizophrenia and substance abuse.