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-HT_1A receptor ligands. All had nanomolar affinities for 5-HT_1A receptors and fully inhibited forskolin-stimulated adenylyl cyclase in-vitro (i.e. the four compounds appeared to be 5-HT_1A agonists). It was also found that the enantiomers of LY-55 behaved as typical 5-HT_1A 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-HT_1A receptors and somatodendritic 5-HT_1A autoreceptors. In contrast, R- and S-LY-49 did not cause any 5-HT_1A receptor-related effects in-vivo except for a partial inhibition of 5-HT synthesis after high doses. The 5-HT_1A 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-HT_1A 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-HT_1A 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-HT_1A 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-HT_1A receptors, both pre- and postsynaptically, compared with S-LY-55. Further studies are, however, needed for a deeper understanding of these differences.     

In-vitro Pharmacology of Sarpogrelate and the Enantiomers of its Major Metabolite: 5-HT2A Receptor Specificity,Stereoselectivity and Modulation of Ritanserin-induced Depression of 5-HT Contractions in Rat Tail Artery

The new antiplatelet agent sarpogrelate (MCI-9042), its major metabolite (R,S)-1-[2-[2-(3-methoxyphe-nyl)ethyl]phenoxy]-3-(dimethylamino)-2-propanol ((R,S)-M-1) and the enantiomers of (R,S)-M-1 were studied as antagonists at 5-HT_2A receptors, 5-HT₁-like receptors, 5-HT₃ receptors, α₁-adrenoceptors, β-adrenoceptors, histamine H₁ receptors, histamine H₂ receptors and muscarinic M₃ receptors in various functional in-vitro assays. Sarpogrelate, (R,S)-M-1, (S)-M-1 and (S)-M-1, respectively, were competitive antagonists of 5-hydroxytryptamine (5-HT) at 5-HT_2A receptors of rat tail artery with calculated pA₂ values of 8·53, 9·04, 9·00 and 8·81, respectively. Sarpogrelate lacked prominent 5-HT_t like, 5-HT₃, β, H_t, H₂ and M₃ antagonist activity and weakly blocked α₁-adrenoceptors (pK_B = 6·30). (S)-M-1 showed weak affinity for 5-HT₁-like receptors (pK_B = 6·30), α₁ (pK_B = 6·80) and β (pK_B = 6·54) adrenoceptors, while (R)-M-1 was a weak antagonist at histamine H₁ receptors (pK_B = 6·49). Stereoselectivity of M-1 enantiomers was low. (R)-M-1 showed 1·6-fold, 2·3-fold and 2·5-fold higher antagonist activity than (S)-M-1 for 5-HT_2A, H₁ and M₃ receptor, respectively. Affinity at β-adrenoceptors and 5-HT₁-like receptors was 5-fold and 3-fold higher for (S)-M-1 than for (R)-M-1. The depression of the maximum effect of 5-HT-induced contractions of rat-tail artery which amounted to 58–72% in the presence of ritanserin (1 nm ), was totally prevented after preincubation with sarpogrelate (1 μm ) and (R)- and (S)-M-1 (30 and 300 nm ), respectively, and partially prevented after preincubation with (R)- and (S)-M-1 (0·3-3 nm ). (R)- and (S)-M-1 failed to differ in restoring the ritanserin-induced depression of the 5-HT maximum response. It is concluded that sarpogrelate, its major metabolite (R, S)-M-1 and M-1 enantiomers are specific antagonists of 5-HT at 5-HT_2A receptors. The stereochemical configuration of the ligands does not seem to be crucial for binding to the 5-HT_2A receptor. Like ketanserin, sarpogrelate and M-1 enantiomers appear to be allosteric activators of the 5-HT_2A receptor system in rat tail artery.     

3-(ω-Aminoalkyl)-5,5-dialkyl(or spirocycloalkyl-1′,5-)hydantoins as New 5-HT1A and 5-HT2A Receptor Ligands

A series of new 3-(ω-aminoalkyl)-5,5-disubstituted hydantoins, containing 1-phenylpiperazine, 1-(o-methoxyphenyl)piperazine or 1,2,3,4-tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5-HT_1A and 5-HT_2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5-HT_1A and 5-HT_2A receptors due to the presence of a 1-arylpiperazine fragment; however, the terminal hydantoin moiety plays an important role in stabilization of the receptor-ligand complex. It has also been found that the two 1-phenylpiperazine derivatives 32 and 36 are new, selective 5-HT_2A receptor ligands (K_i = 34 and 37 nM, respectively), whereas the derivative of 1-(o-methoxyphenyl)piperazine ( 38 ) is a new, highly potent 5-HT_1A receptor ligand (K_i = 0.51 nM) with a moderate affinity for 5-HT_2A receptors (K_i = 213 nM).