Synthesis, resolution and radioiodination of S(−)trans-5-hydroxy-2-[N-n-propyl-N-(3′-iodo-2′-propenyl)amino]tetralin-S(−)trans-5-OH-PIPAT: A new dopamine D2-like receptor ligand

✍ Scribed by Sumalee Chumpradit; Mei-Ping Kung; Janet Vessotskie; Hank F. Kung

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: French
• Weight: 579 KB
• Volume: 36
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580361105

✦ Synopsis

Abstract

A new dopamine D2‐like receptor ligand, (R,S)trans‐5‐hydroxy‐2‐[N‐n‐propyl‐N‐(3′‐iodo‐2′‐propenyl)amino]tetralin ((R,S)trans‐5‐OH‐PIPAT, 3), based on high affinity dopamine receptor agonist 5‐hydroxy‐2‐[N,N‐(di‐n‐propyl)‐2‐amino]tetralin (5‐OH‐DPAT, 1). was prepared. The synthesis was achieved by a reductive amination of 5‐methoxy‐2‐tetralone with n‐propylamine, followed by N‐alkylation, to afford 5‐methoxy‐N‐propyl‐N‐2′‐propynyl‐2‐aminotetralin, 7. Reduction of 7 with tributyltin hydride gave the tri‐n‐butyl tin derivative, 8, which was converted to 9 by an iododemetalation reaction. Demethylation of 9 gave the desired compound, (R,S)trans‐5‐OH‐PIPAT, 3. The resolved (R) and (S)trans‐5‐OH‐PIPAT, 3 were also quantitatively prepared. In vitro binding studies showed the stereoselectivity of this new compound for binding to dopamine D2‐like receptors. S(‐)‐3 displayed high binding affinity, with inhibition constants (K~i~) of 0.38, 0.09 and 0.67 nM for dopamine D2H (expressed in HEK293 cells), D3 (expressed in Sf9 cells) and D4H receptors (expressed in CHO cells), respectively. Using the same binding assays, the less active R(+) isomer displayed K~i~ values of 7.29, 4.87 and 16.44 nM for D2H, D3 and D4H receptors, respectively. In addition, radiolabeling was successfully performed, either with the racemic tin derivative, (R,S)‐11, or using the optically resolved tin derivatives R(+)‐or S(‐)‐111, to give the final radiolabeled product, [125I]R(+) or S(‐)‐3.