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

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.