Geometry-affinity relationships of the selective serotonin receptor ligand 9-(aminomethyl)-9,10-dihydroanthracene.
With the exception of its two aromatic rings and basic nitrogen atom, 9-(aminomethyl)-9,10-dihydroanthracene (AMDA; 1) is remarkably devoid of the pharmacophore features usually associated with high-affinity receptor ligands such as the heteroatom hydrogen bonding features of the endogenous ligand serotonin. AMDA does contain a phenylethylamine skeleton within a tricyclic ring system, and the presence of the second aromatic group is necessary for optimal receptor affinity. The structural requirements for the binding of AMDA at 5-HT(2A) receptors were investigated with respect to the geometric relationship between the two aromatic rings. It appears that the geometry of the AMDA parent is in the optimal range for fold angle between aromatic moieties. Evaluation of conformationally constrained derivatives of AMDA suggests that a chain extended trans, gauche form is most likely responsible for high affinity.
Runyon
Scott P
SP
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Peddi
Srinivas
S
Savage
Jason E
JE
Roth
Bryan L
BL
Glennon
Richard A
RA
Westkaemper
Richard B
RB
D016475:3T3 Cells; D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
C122082:9-(aminomethyl)-9,10-dihydroanthracene; D000873:Anthracenes; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin