Spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine-a structurally unique tetracyclic 5-HT2A receptor antagonist.
Structural elaboration of phenylethylamine to spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine (SpAMDA) produces an agent with unexpectedly high affinity (K(i)=4 nM) at 5-HT(2A) receptors. It was shown that SpAMDA acts as a 5-HT(2A) receptor antagonist. The structure and molecular geometry of SpAMDA are not consistent with existing pharmacophore features, and a novel 5-HT(2A) antagonist pharmacophore model is proposed for the binding of aminomethyl-9,10-dihydroanthracene analogs. Thus, SpAMDA may be a structurally novel parent of a new class of 5-HT(2A) receptor antagonists that binds to the receptor in a unique fashion that is distinct from the binding topology of existing 5-HT(2A) receptor antagonists.
Peddi
Srinivas
S
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Box 980540, Richmond, VA 23298-0540, USA.
Roth
Bryan L
BL
Glennon
Richard A
RA
Westkaemper
Richard B
RB
D016475:3T3 Cells; D000818:Animals; D000873:Anthracenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000873:Anthracenes; D011759:Pyrrolidines; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists