Structural determinants for high 5-HT2A receptor affinity of spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SpAMDA)

The synthesis and 5-HT2A receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (4), a structurally unique tetracyclic 5-HT2A receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT2A receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT2A receptor affinities. In addition, the parent compound is shown to have high 5-HT2 receptor selectivity.