(Tétrahydro-1,2,3,6 pyridinyl-4)-3 1H-indoles: synthèse, propriétés sérotoninergique et anti-dopaminergiques

Three-dimensional quantitative structure-activity relationships of 5-HT receptor binding data for tetrahydropyridinylindole derivatives: a comparison of the Hansch and CoMFA methods

“…(2) From a subset consisting of 15 4-THPI analogs (4-18, marked with an asterisk (*) in Table I) which vary only in their 5-substituent, Taylor et aV derived QSAR eqs 4 and 6: -6.9169 + 0.0400V5-0.0573 log (lo(l,5-23'2) + 1) (for 5-HT1A pK;) (4) pK{ = 4.4575 -0.0281 V5 + 0.9022 log P (for 5-HT2 pKj) (6) We have used these previously derived equations to predict the activity of 12 of our new compounds, 27-37 and 44, which also vary only in their indole 5-substituent (indicated) by double dagger (|) in Table I). In order to compare the predictive ability of CoMFA vs Hansch analysis, the pK, values for the above mentioned 12 compounds (27-37 and 44) and were also predicted from a separate CoMFA derived from the same subset of 15 4-THPI analogs (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). It should be noted that there are several reasons why this comparison was performed using the above eq 4 and 6 rather than eqs 5 and 7 from Taylor et al,7 which were the "best" reported equations, including a minor electronic component, with r2 values around 0.88 as opposed to around 0.75 for eqs 4 and 6.…”

“…The prototype for this series of compound, RU 24969 (1, Table I), is the most thoroughly investigated of a number of derivatives of 4-THPI that have been previously examined for dopaminergic and 5-HT agonist activity. [1][2][3][4] Binding studies suggest that RU 24969 is relatively selective for 5-HTia and 5-HTib sites6'6 with lesser activity at 5-HTic, 5-HT2, and 5-HTid sites.6 '6 In a previous study,7 we used a series of 4-THPI analogs to investigate steric, electronic and hydrophobic requirements for recognition at 5-HTia and 5-HT2 receptor binding sites. In that study, the pKi values of different analogs were quantitatively related to various structural descriptors by applying a modified Hansch approach to a set of over 25 substituted 4-THPI.…”

Characterization of [3H]CP‐96,501 as a Selective Radioligand for the Serotonin 5‐HT1B Receptor: Binding Studies in Rat Brain Membranes

“…Although the THPindoles were investigated originally as serotonin and dopamine agonists (Guillaume et al, 1987), we found low binding affinities for RU 24969 and its demethyl derivative (3-THP-5-hydroxyindole) at dopamine receptors with either N- [3H]propylnorapomorphine (ICs0, 14 and 3.1 pM, respectively) or [3H]spiperone (ICsO, 10 and 2.6 pM, respectively) binding. The same two 3-THPindoles also showed very weak inhibition of [3H]prazosin ( a l ; ICs0, 5.5 and 8.7 pM, respectively) and p- son, we obtained a B,,, of 73 t 2 fmol/mg protein ( K D , 2.6 k 0.1 nM, n = 3) in rat whole-brain tissue using [3H]5-HT (Peroutka, 1986).…”

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2☆

“…The nitrogen in the imide group of compounds 4a-4i was alkylated with 1,4-dibromobutane to form bromobutyl derivatives 5a-5i, which were subsequently hydrogenated to form 5,6,7,8-tetrahydro derivatives (6a-6i). The final compounds (8a-8u) were obtained by the condensation of bromobutyl derivatives 6a-6i with the appropriate piperidyl-indole (7a-7c) synthesized according to the method previously described [25].…”

“…Modifications were performed in the pharmacophore portion where the 3-(4-piperidyl)-1H-indole group or its 5-methoxy or 2-methyl derivative was inserted. These groups reveal the molecule's potential to inhibit the serotonin transporter (SERT) protein, as well as bind 5-HT 1A receptors [24][25][26]. The pharmacophore portion of the molecule was bound to the terminal tetrahydro-pyrido [1,2-c]pyrimidine moiety by an n-butyl chain.…”