Structural elaboration of phenylethylamine to 9-(aminomethyl)-9,10-dihydroanthracene (AMDA) produces an agent with high affinity (K-i = 9.5-21 nM) at 5-HT2A receptors. It was shown that AMDA acts as a 5-HT2A receptor antagonist. The structure and molecular geometry of AMDA are not consistent with existing pharmacophore models for 5-HT2A receptor antagonist activity. Thus, AMDA may be a structurally novel parent of a new class of 5-HT2A receptor antagonists that binds to the receptor in a unique fashion that is distinct from the binding topology of existing 5-HT2A receptor antagonists. (C) 1999 Elsevier Science B.V. All rights reserved.