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Synthesis of [N‐C 3 H 3 ]‐ trans ‐(1 R ,3 S )‐(−)‐1‐Phenyl‐3‐N,N‐dimethylamino‐1,2,3,4‐tetrahydronaphthalene (H 2 ‐PAT)
Author(s) -
Wyrick Steven D.,
Myers Andrew M.,
Booth Raymond G.,
Kula Nora S.,
Baldessarini Ross J.,
Mailman Richard B.
Publication year - 1994
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.2580340205
Subject(s) - chemistry , tyrosine hydroxylase , stereochemistry , sigma receptor , tritium , enantiomer , receptor , chemical synthesis , dopamine , specific activity , in vitro , enzyme , biochemistry , medicine , physics , nuclear physics
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.