C8-Substituted derivatives of 2-(dipropylamino)tetralin: exploration of the effect of C8-aryl and heteroaryl substituents on the interaction with 5-HT1A-receptor

Liu, Y; Cortizo, Lourdes; Yu, Hong; Svensson, Björn E.; Lewander, Tommy; Hacksell, Uli

doi:10.1016/0223-5234(96)88236-5

Cited by 3 publications

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“…The results from the original in-vivo screening (Liu et al , 1995 have been confirmed by the findings of dosedependent typical S-HTIA agonist-like effects induced by Rand S-LY-55. Thus, these two compounds elicited flat body posture, hypothermia and a reduction in 5-HT turnover.…”

Section: Discussionmentioning

confidence: 72%

“…In contrast, the enantiomers of LY-55 appear to be better agonists at 5-HTIA receptors both pre-and postsynaptically in-vivo and they seem to be transported more readily across the blood-brain barrier. It is possible that other C8-aryl and heteroaryl substituted 2-(di-propy1amino)tetralins devoid of pharmacological effects invivo (Liu et al 1995) might have pharmacodynamic and pharmacokinetic properties similar to R-LY-49.…”

Section: Discussionmentioning

confidence: 99%

“…It is, therefore, of interest to understand fully the functional role of this 5-HT receptor subtype. Starting from the original finding of the 5HTergic action of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; Arvidsson et a1 1981;Hjorth et a1 1982), we have studied enantiopure dipropylaminotetralin derivatives to further the understanding of the interaction between the 5-HTIA receptor and its ligands and to find new chemical entities of interest for drug development (Liu et al , 1995Hacksell et a1 1993). In the process of screening a series of C8-substituted dipropylaminotetralins, we identified compounds that had nanomolar affinity for the 5-HTIA receptor in a receptorbinding assay in-vitro, but lackqd the ability to stimulate or block ~-H T~A receptors in-vivo (Liu et a1 1993(Liu et a1 , 1995.…”

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confidence: 99%

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Pharmacodynamic and Pharmacokinetic Studies in Rats of S-8-(2-Furyl)- and R-8-Phenyl-2-(di-n-Propylamino)Tetralin, Two Novel 5-HT1A Receptor Agonists In-vitro with Different Properties In-vivo

Liu

et al. 1997

Journal of Pharmacy and Pharmacology

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R- and S-8-(2-Furyl)- and R- and S-8-phenyl-2-(di-n-propylamino)tetralins (R- and S-LY-55 and R- and S-LY-49, respectively), novel enantiopure dipropylaminotetralins, have been screened as 5-HT1A receptor ligands. All had nanomolar affinities for 5-HT1A receptors and fully inhibited forskolin-stimulated adenylyl cyclase in-vitro (i.e. the four compounds appeared to be 5-HT1A agonists). It was also found that the enantiomers of LY-55 behaved as typical 5-HT1A receptor agonists in rats in-vivo by inducing a typical behavioural 5-HT syndrome, hypothermia and a decrease in 5-HT synthesis and turnover, indicating effects both on postsynaptic 5-HT1A receptors and somatodendritic 5-HT1A autoreceptors. In contrast, R- and S-LY-49 did not cause any 5-HT1A receptor-related effects in-vivo except for a partial inhibition of 5-HT synthesis after high doses. The 5-HT1A receptor antagonist WAY-100635 was shown to attenuate the R-LY-49-induced inhibition of 5-HT synthesis, indicating the compound to be a weak agonist at somatodendritic 5-HT1A autoreceptors. R-LY-49 at a high dose and with a long pre-treatment time interval inhibited the hypothermic and behavioural effects, but not the inhibition of 5-HT synthesis induced by the 5-HT1A receptor agonist R-8-hydroxy-(dipropylamino)tetralin (R-8-OH-DPAT). Taken together, these findings seem to indicate, that R-LY-49 is a weak partial agonist at 5-HT1A receptors. A comparative pharmacokinetic study showed that the enantiomers of LY-55 entered the brain rapidly after subcutaneous administration and reached peak brain tissue/plasma concentration ratios within 15-30 min of injection, whereas the brain concentrations of R-LY-49 increased slowly, reaching a relatively low peak brain tissue/plasma concentration ratio 90 min after injection despite their similar lipophilicity. The differences between the pharmacological activity of the two compounds in-vivo seem to be explained by their different abilities to cross the blood-brain barrier, and a weak agonistic activity of R-LY-49 on 5-HT1A receptors, both pre- and postsynaptically, compared with S-LY-55. Further studies are, however, needed for a deeper understanding of these differences.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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