Design and Synthesis of Substituted Dihydrofuranochromans as New Serotonergic Molecular Probes

Two chemical probes (4, 5) for the agonist binding sites of serotonin 5-HT2A and 5HT2C receptors were designed as rigid analogs of the methoxylated hallucinogenic phenylalkylamines. These drugs, hybrids of previously constructed heterocycles, include 5and 6-membered oxygen-containing rings that restrict the conformational freedom of the alkoxy ring substituents. Various strategies were explored in an attempt to synthesize the new compounds. Specifically, one method involving a reduction/diazotization/substitution sequence and two alternate phenol alkylation methods were employed. Although target molecules 4 and 5 have not yet been prepared, significant progress has been made toward their synthesis with the construction of a key tricyclic intermediate (6) via a unique ether-cleavage reaction, and our efforts are reported here. Ultimately, pharmacological testing of 4 and 5 will provide more detailed information about the three-dimensional structure and topography of the agonist binding sites in serotonin 5-HT2 receptors. INTRODUCTION Previous investigations into the topography of the agonist binding sites of the 5-HT2A and 5-HT2C serotonin receptor subtypes have used molecular probes of general structure 1. These hallucinogenic phenylalkylamines contain the essential structural features required for high-affinity binding to 5-HT2A and 5-HT2C agonist sites. However, the directionality of the oxygen lone-pair electrons involved in putative hydrogen-bonding interactions at the receptor sites could not be confirmed due to free rotation about the arene-oxygen bonds in these compounds. Structure–activity relationship (SAR) studies of a series of heterocyclic, conformationally-restricted analogs of 1 ultimately revealed that molecular probe 2 possessed the optimum orientation of the arene oxygen lone-pair electrons. In that work, rat behavioral and in vitro radioligand binding assays clearly showed that 2 is a potent and selective sero-