Synthesis of (+)-(R)- and (-)-(S)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)] aminotetralin: new 5-HT1A receptor ligands.
(R,S)-trans-8-Hydroxy-2-[N-n-propyl-N-(3'-iodo-2'- propenyl)amino]tetralin 7, a new radioiodinated ligand based on 8-OH-DPAT, was reported as a potential ligand for 5-HT1A receptors. The optically active (+)-(R)- and (-)-(S)-7 were prepared to investigate the stereoselectivity of (R,S)-7. Racemic intermediate 8-methoxy-2-N-n-propyltetralin was reacted with the acyl chloride of (-)-(R)-O-methylmandelic acid to form a mixture of (S,R)- and (R,R)-diastereoisomers, which were separated by flash column chromatography. After removing the N-acyl group from the diastereoisomers, the desired (+)-(R)- or (-)-(S)-7 was obtained by adding an N-iodopropenyl group. In vitro homogenate binding studies showed the stereoselectivity of this new compound for 5-HT1A receptors. (+)-(R)-7 isomer displayed 100-fold higher affinity than the (-)-(S)-7 isomer. Biochemical study indicated that (+)-(R)-7 potently inhibited forskolin-stimulated adenylyl cyclase activity in hippocampal membranes (Emax and EC50 were 24.5% and 5.4 nM, respectively), while (-)-(S)-7 showed no effect at 1 microM. The radioiodinated (+)-(R)- and (-)-(S)-[125I]7 were confirmed by coelution with the resolved unlabeled compound on HPLC (reverse phase column PRP-1, acetonitrile/pH 7.0 buffer, 80/20). The active isomer, (+)-(R)-[125I]7, displayed high binding affinity to 5-HT1A receptors (Kd = 0.09 +/- 0.02 nM). In contrast, the (-)-(S)-7 isomer displayed a significantly lower affinity to the 5-HT1A receptor (Kd > 10 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
Zhuang
Z P
ZP
Department of Radiology, University of Pennsylvania, Philadelphia 19104, USA.
Kung
M P
MP
Clarke
W
W
Maayani
S
S
Mu
M
M
Kung
H F
HF
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000201:enzymology; D066298:In Vitro Techniques; D008024:Ligands; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D013764:Tetrahydronaphthalenes; C083828:8-hydroxy-2-(N-n-propyl-N-(3'-iodo-2'-propenyl)amino)tetralin