Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(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)
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PMID:Synthesis of (+)-(R)- and (-)-(S)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)] aminotetralin: new 5-HT1A receptor ligands. 757 52

A rapid, sensitive and enantioselective HPLC assay for the simultaneous determination of the reference 5-HT1A receptor agonists, R-(+)- and S-(-)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT and S-8-OH-DPAT, respectively), in rat blood is presented. A selective extraction procedure was developed using a preliminary sample clean-up followed by isolation of R- or S-8-OH-DPAT on mixed-mode NARC-2 solid-phase columns. Separation of the enantiomers was performed by high-performance liquid chromatography using a Chiracel OD-R column. Detection was obtained using an electrochemical detector set at a voltage of 0.63 V. The mobile phase consisted of a 50 mM phosphate buffer (pH 5.5)-acetonitrile (80:20, v/v) mixture. At a flow-rate of 1 ml min(-1), the total run time was approximately 14 min. The limit of detection for R- and S-8-OH-DPAT was 0.5 ng ml(-1). In the concentration range between 50 ng ml(-1) and 1000 ng ml(-1) intra- and inter-day relative standard deviations were less than 12%. The assay was applied to a pharmacokinetic-pharmacodynamic study in rats in which decrease of body temperature was used as a measure of 5-HT1A receptor-mediated effect. Values for clearance, volume of distribution at steady state and terminal elimination rate constant were 22+/-2 ml min(-1), 1969+/-473 ml and 156+/-34 min for R-8-OH-DPAT and 16+/-1 ml min(-1), 3353+/-347 ml and 334+/-36 min for S-8-OH-DPAT, respectively. No enantiomeric interconversion was observed in vivo from R-8-OH-DPAT to S-8-OH-DPAT or vice versa.
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PMID:Enantioselective high-performance liquid chromatographic analysis of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Application to a pharmacokinetic-pharmacodynamic study in rats. 1077 27