Synthesis of [N-C3H3]-trans-(1R,3S)-(−)-1-Phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene (H2-PAT)

✍ Scribed by Steven D. Wyrick; Andrew M. Myers; Raymond G. Booth; Nora S. Kula; Ross J. Baldessarini; Richard B. Mailman

• Publisher: John Wiley and Sons
• Year: 1994
• Tongue: French
• Weight: 210 KB
• Volume: 34
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580340205

✦ Synopsis

Abstract

Subsequent to the discovery that the (+)‐benzomorphan sigma receptor ligands, (+)‐pentazocine and (+)‐N‐allylnormetazocine, stimulated tyrosine hydroxylase activity and dopamine synthesis in rat striatum in vitro, we reported a similar effect on a structurally similar series of 1‐phenyl‐3‐aminotetrahydronaphthalenes (phenylaminotetralins, PAT's). Both racemic 1‐phenyl‐3‐dimethylamino‐6‐chloro‐7‐hydroxytetralin (CI,OH‐PAT) and racemic 1‐phenyl‐3‐dimethylaminotetralin (H~2~‐PAT) stimulated tyrosine hydroxylase with an EC~50~ of approximately 0.1 μM. The former was also found to have a non‐specific dopamine releasing effect while the latter was devoid of such activity affording it the less complicated pharmacological profile of the two analogs. We previously reported the synthesis of tritium labeled Cl,OH‐PAT to be used in radioreceptor and autoradiography studies and found that it labeled a sigma‐like site in guinea pig brain with an apparent Kd of ∼50 pM and with a pharmacological profile unique from other known CNS receptors. Here we report the synthesis of high specific activity tritium labeled trans‐(1__R__,3__S__)‐(−)‐H~2~‐PAT as this enantiomer was found to be more active in the tyrosine hydroxylase assay and possessed approximately 45 fold greater affinity for the novel neuromodulatory sigma‐like receptor.