New norepinephrine potentiators: synthesis and structure-activity relationships of a series of 4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols.
A variety of 1,2,3,4-tetrahydroisoquinolin-4-ols (1-6) were prepared as part of our search for new norepinephrine (NE) potentiators and to clarify the structure-activity relationships. These compounds and some previously prepared compounds were compared with 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (PI-OH) (1a) for ability to potentiate NE. The potency, for 2-substitution, was found to be in the order: Me > Et > iso-Pr > H. The compounds substituted by a halogen atom at the para position in the 4-phenyl group of PI-OH showed greater activities than did PI-OH, and the observed order of potency for the substitution was Cl > Br > F > H. The compound (4) methylated at the hydroxy group in PI-OH had greatly diminished activity. Although the desoxy compound (6) of PI-OH potentiated the response to NE at low concentrations, the potentiation was progressively masked by an inhibitory activity as the concentration of 6 was increased. In addition, the 4-cyclohexyl analogue (5) failed to potentiate NE. These results show the importance of the beta-phenylethanolamine skeleton of PI-OH for producing NE potentiation without accompanying inhibitory action. The racemic 4-chlorophenyl analogue (2a) was resolved by HPLC to (R)-(+)-2a and (S)-(-)-2a. The NE-potentiating activity was found to reside exclusively in (R)-(+)-2a, which had the highest activity among compounds tested in this study; the activity ratio was 25 at 3 x 10(-6) M. The antidepressant activity of racemic 2a was evaluated by a forced swimming test.(ABSTRACT TRUNCATED AT 250 WORDS)
Kihara
M
M
Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
Kashimoto
M
M
Kobayashi
Y
Y
Nagao
Y
Y
Moritoki
H
H
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004357:Drug Synergism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009132:Muscles / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D007546:Isoquinolines; D009638:Norepinephrine