9-Aminomethyl-9,10-dihydroanthracene (AMDA) analogs as structural probes for steric tolerance in 5-HT2A and H1 receptor binding sites.
Synthesis, radioligand binding and molecular modeling studies of several 9-aminomethyl-9,10-dihydroanthracene (AMDA) analogs were carried out to determine the extent of the steric tolerance associated with expansion of the tricyclic ring system and amine substitution at 5-HT(2A) and H(1) receptors. A mixture of (7,12-dihydrotetraphene-12-yl)methanamine and (6,11-dihydrotetracene-11-yl)methanamine in a 75-25% ratio was found to have an apparent K(i) of 10nM at the 5-HT(2A) receptor. A substantial binding affinity for (7,12-dihydrotetraphene-3-methoxy-12-yl)methanamine at the 5-HT(2A) receptor (K(i)=21 nM) was also observed. Interestingly, this compound was found to have 100-fold selectivity for 5-HT(2A) over the H(1) receptor (K(i)=2500 nM). N-Phenylalkyl-AMDA derivatives, in which the length of the alkyl chain varied from methylene to n-butylene, were found to have only weak affinity for both 5-HT(2A) and H(1) receptors (K(i)=223 to 964 nM). Our results show that large rigid annulated AMDA analogs can be sterically accommodated within the proposed 5-HT(2A) binding site.
Shah
Jitesh R
JR
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Mosier
Philip D
PD
Peddi
Srinivas
S
Roth
Bryan L
BL
Westkaemper
Richard B
RB
D000873:Anthracenes / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D006801:Humans; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C122082:9-(aminomethyl)-9,10-dihydroanthracene; D000873:Anthracenes; D044402:Receptor, Serotonin, 5-HT2A; D044263:Receptors, Serotonin, 5-HT1