Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT2A/2C receptor agonists

The affinity of ligands for either the 5-HT2A or 5-HT2C agonist binding sit e was enhanced by modification of the 2,5-oxygen substituents that are foun d in typical hallucinogenic amphetamines such as 4b (DOB). Restriction of t he conformationally flexible a,fi-dimethoxy substituents into fused dihydro furan 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 heter ocyclic nucleus 7 with N-trifluoroacetyl-protected D- or L-alanyl chloride, followed by ketone reduction and N-deprotection. The enantiomers demonstra ted modest stereoselectivity at the two receptors. Several general trends w ithin these classes of new compounds were observed during their pharmacolog ical investigation. For most pairs of optical isomers tested, the R-enantio mers of the compounds containing heterocycle 7 bound with only slightly hig her affinity than their S-antipodes at the 5-HT2A and 5-HT2C receptors. Lik ewise, functional studies indicated that the R-enantiomers generally displa yed increased potency compared to the S-enantiomers. Aromatization of the d ihydrofuran rings of these arylalkylamines further increased affinity and p otency. Only a few compounds were full agonists with most of them possessin g 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-HT2A receptor reported to date.