Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT_2A/2C Receptor Agonists

Abstract

The affinity of ligands for either the 5-HT(2A) or 5-HT(2C) agonist binding site was enhanced by modification of the 2,5-oxygen substituents that are found in typical hallucinogenic amphetamines such as 4b (DOB). Restriction of the conformationally flexible 2,5-dimethoxy substituents into fused dihydrofuran rings generally resulted in increased potency relative to the parent 2,5-dimethoxy compounds. The pure enantiomers of these arylalkylamines were obtained by enantiospecific synthesis that involved acylation of the heterocyclic nucleus 7 with N-trifluoroacetyl-protected D- or L-alanyl chloride, followed by ketone reduction and N-deprotection. The enantiomers demonstrated modest stereoselectivity at the two receptors. Several general trends within these classes of new compounds were observed during their pharmacological investigation. For most pairs of optical isomers tested, the R-enantiomers of the compounds containing heterocycle 7 bound with only slightly higher affinity than their S-antipodes at the 5-HT(2A) and 5-HT(2C) receptors. Likewise, functional studies indicated that the R-enantiomers generally displayed increased potency compared to the S-enantiomers. Aromatization of the dihydrofuran rings of these arylalkylamines further increased affinity and potency. Only a few compounds were full agonists with most of them possessing intrinsic activities in the range of 60-80%. These compounds with a fully aromatic linear tricyclic nucleus are some of the highest-affinity ligands for the 5-HT(2A) receptor reported to date.

Structure–activity relationships of serotonin 5‐HT2A agonists

“…A similar approach to tethering of the 2-methoxy into a dihydrofuran also led to a very potent compound (49), 83 but when both the 2-and 5-methoxy functions were incorporated into dihydrofuran rings, the result was a series of exceptionally potent 5-HT 2A/2C agonists exemplified by 50, 83,84 which had an affinity of 0.48 nM for the cloned human 5-HT 2A receptor. Aromatization of the dihydrofuran rings to afford 51 led to even further enhancement of affinity and potency ( Figure 21).…”

Serotonin 5-Hydroxytryptamine2AReceptor-Coupled Phospholipase C and Phospholipase A2Signaling Pathways Have Different Receptor Reserves

“…3 H]AA release were determined from two separate assay plates, the assays were conducted side-by-side in cells seeded from the same cell population and, most importantly, without any experimental interventions that would eliminate one signaling pathway, consistent with the designation of an intact system as proposed by Leff et al (1997 To determine the effect of distinct structural motifs on liganddirected pathway activation, we used a series of agonists from the tryptamine, phenethylamine, and ergoline families with known partial agonist activities in naturally expressed 5-HT 2A receptors or heterologous cell lines (Sanders-Bush et al, 1988;Zifa and Fillion, 1992;Chambers et al, 2001; D. KurraschOrbaugh and D. E. Nichols, unpublished results; Fig. 4).…”

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors

“…[188] In a later study, conformationally restricted analogues were evaluated for their functional activity at 5-HT 2A receptors using a PI hydrolysis assay. [189] In this assay, parent compound (AE )-DOB (15, EC 50 = 72 nm; 79 % of maximal 5-HT stimulation) was less potent than R-(À)-39 (EC 50 = 8.38 nm; 80 % of maximal 5-HT stimulation) while the most potent ligand was R-(À)-40 (EC 50 = 2.7 nm; 93 % of 5-HT stimulation). As with the original phenylalkylamines, the R-(À) enantiomer of these conformationally restricted analogues generally displayed increased activity and binding affinity.…”