Synthesis and structure activity relationships of cis- and trans-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-c]pyridines for 5-HT receptor subtypes.
A series of cis- and trans-fused hexahydroindeno[2,1-c]pyridines have been prepared and evaluated for affinity and selectivity at the 5-HT1A subtype of the serotonin receptor. Using molecular modeling studies we predicted that the 5-methoxy-trans-fused members of this class would exhibit affinity for this site. In agreement with these predictions, trans-5-methoxy-N-propyl-2,3,4,4a,9,-9a-hexahydro-1H-indeno[2,1-c]pyridi ne (6a) demonstrated moderate affinity and high selectivity for the 5-HT1A binding site, whereas the cis-fused isomer 5a demonstrated virtually no affinity at this site. Additional trans-fused analogs from this series, where the nitrogen was substituted with a variety of alkylene imide containing appendages, demonstrated high (0.60-51 nM) affinity and excellent selectivity for the 5-HT1A site. Certain of these analogs, independent of ring-fusion stereochemistry, also demonstrated high affinity for the 5-HT2 binding site.
Meyer
M D
MD
Abbott Laboratories, Abbott Park, Illinois 60064.
DeBernardis
J F
JF
Hancock
A A
AA
D001665:Binding Sites; D001667:Binding, Competitive; D015195:Drug Design; D007192:Indenes / Q000138:chemical synthesis / Q000378:metabolism; D007650:Ketanserin / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
D007192:Indenes; D011725:Pyridines; D011985:Receptors, Serotonin; C085374:5-methoxy-N-propyl-2,3,4,4a,9,9a-hexahydro-1-H-indeno(2,1-c)pyridine; D012701:Serotonin; D007650:Ketanserin