Resolved N,N-dialkylated 2-amino-8-hydroxytetralins: stereoselective interactions with 5-HT1A receptors in the brain

Abstract

The enantiomers of the N,N-dimethylamino (1), N,N-diethylamino (2), and N,N-dibutylamino (4) derivatives of 8-hydroxy-2-(dipropylamino)tetralin (8-OH DPAT; 3) have been synthesized. The compounds have been tested for activity at central 5-hydroxytryptamine and dopamine receptors by use of biochemical and behavioral tests in rats. In addition, the ability of the enantiomers of 1-4 to displace [3H]-8-OH DPAT from 5-HT1A binding sites was evaluated. Rank order of potencies in the in vivo tests corresponded to that observed in the 5-HT1A binding assay. In all three tests, the enantiomeric potency ratio was about 10 for 1 and 2 and only around 2-4 for 3 and 4. The more potent enantiomer of 1-3 had the R configuration. In contrast, (S)-4 seemed to be slightly more potent than (R)-4.

Inhibition of Bladder Activity by 5-Hydroxytryptamine1 Serotonin Receptor Agonists in Cats with Chronic Spinal Cord Injury

“…In our previous study (Thor et al, 2002), we used a racemic (R,S) mixture. Some data indicate a difference in the effectiveness of (R)-and (S)-enantiomers (Bjork et al, 1989;Cornfield et al, 1991); however, our preliminary studies (not shown) revealed no cystometric difference. 8-OH-DPAT and WAY-100635 (Sigma-Aldrich) were dissolved in distilled water.…”

In 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Primates, the Selective 5-Hydroxytryptamine 1a Agonist (R)-(+)-8-OHDPAT Inhibits Levodopa-Induced Dyskinesia but Only with\ Increased Motor Disability

“…R,S-(Ϯ)-8-hydroxydipropylaminotetralin [(Ϯ)-8-OHDPAT] is another 5-HT 1a agonist that also acts on dopaminergic and 5-HT 7 receptors (Arnt and Hyttel, 1986;Eglen et al, 1997). In contrast, (R)-(ϩ)-8-hydroxy-DPAT [(ϩ)-8-OHDPAT], the more potent enantiomer of (Ϯ)-8-OHDPAT, is a highly selective 5-HT 1a agonist lacking any marked activity on dopaminergic receptors (Middlemiss and Fozard, 1983;Bjork et al, 1989;Cornfield et al, 1991), although it possesses some partial agonistic effects on 5-HT 7 receptors (Tsou et al, 1994;Wood et al, 2000).…”

Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats

“…However, several biochemical, electrophysiological and behavioural studies have shown that (R)-8-OH-DPAT is about two times more potent than the (S)-8-OH-DPAT enantiomer, suggesting the former is a full agonist, while the latter acts as a partial agonist. Thus, (R)-8-OH-DPAT was more potent in inhibition of 5-HT biosynthesis (Arvidsson et al, 1981;Bjork et al, 1989), inhibition of forskolin-stimulated cAMP synthesis (Cornfield et al, 1991;Foreman et al, 1995), stimulation of h5-HT 1A receptor-mediated G-protein activation (Lejeune et al, 1997), suppressing the firing activity of hippocampal CA3 neurons (Hadrava et al, 1996) or serotonergic neurons in the dorsal raphe nucleus (DRN) (Lejeune et al, 1997). In addition, the racemate and both enantiomers were shown to exert 5-HT reuptake inhibiting properties (Assie and Koek, 1996) and additional affinity, particularly of (R)-8-OH-DPAT, towards the non-5-HT 1A receptor binding sites in the raphe nucleus (Assie and Koek, 2000).…”