A New Class of Arylpiperazine Derivatives:  the Library Synthesis on SynPhase Lanterns and Biological Evaluation on Serotonin 5-HT_1A and 5-HT_2A Receptors

Abstract

An efficient solid-supported method for the synthesis of a new class of arylpiperazine derivatives containing amino acid residues has been developed. A 72-membered library was synthesized on SynPhase Lanterns functionalized by a BAL linker. A one-pot cleavage/cyclization step of aspartic and glutamic acid derivatives yielded succinimide- and pyroglutamyl-containing ligands (chemsets 9 and 10). The library representatives under study showed different levels of affinity for 5-HT(1A) and 5-HT(2A) receptors (estimated K(i) = 24-4000 and 1-2130 nM, respectively). Several dual 5-HT(1A)/5-HT(2A) ligands were found, of which two (9(3,3) and 9(3,5)) displayed high 5-HT(2A) affinity comparable to that of the reference drug ritanserin. A set of individual fragment contributions for the prediction of 5-HT(1A) and 5-HT(2A) affinity of all the library members were defined on the basis of the Free-Wilson analysis of 26 compounds. An alkylarylpiperazine fragment had essentially the same impact on the affinity for both receptors, whereas different terminal amide fragments were preferred by 5-HT(1A) (chemset 17, R(2) = adamantyl) and 5-HT(2A) (chemset 9, R(2) = norborn-2-ylmethyl) binding sites.

Synthesis of new compounds containing the pyrazolo[3,4‐b]pyridine‐3‐one subunit

“…THF was freshly distilled from Na/ benzophenone, while CH 2 Cl 2 was distilled over CaH 2 . The biological characterization of the compounds was based on the screening protocol described by Zajdel et al [14,15].…”

“…The medium was hydrolyzed then the solution was extracted with CH 2 Cl 2 . The organic phases were dried over MgSO 4 6-(2-(Dibutylamino)ethyl)-4-methyl-2-phenyl-1,2-dihydropyrazolo [3,4-b]pyridin-3-one (15). One hundred and sixty milligrams (0.32 mmol; 1 eq) of compound 13 were dissolved in 5 mL of TFA then the solution was heated at reflux during 5 h. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: methanol/ethyl acetate, 1:9 Butyl.2-(1-(4-methoybenzyl)-6-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazolo [3,4-b]pyridin-4-yl)acetate (17).…”

Synthesis and TGF‐β Receptor Binding Inhibition of Multibranched Compounds

“…Radiofrequency encoding of Synphase Crowns were used with Transtems and Transort software to manage a split and pool synthesis for obtaining library C [13] instead of using Multipin 8 Â 12 parallel array. Thus, Synphase Crowns which had to remain unreacted were sorted apart from those having to react with Fmoc-Asp(OtBu)-OH at step 1 or Fmoc-Ala-OH at step 3.…”

Solid‐Phase Synthesis of Aryl‐Alkylamine Derivatives Using Protected Aminoalcohol Building Blocks on SynPhaseTM Lanterns

“…Among the currently available techniques for the generation of compound libraries, solid-phase synthesis has proven to be a powerful, time-and cost-effective tool. A successful application of this technique was demonstrated in several reviews [1 -3], as well as in the course of our recent studies aimed at discovering new arylpiperazines modified with N-acylated amino acid residues as potential ligands of 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors [4,5].…”

“…All the building blocks were selected according to the literature survey, as well as on the basis of our own research in the area of potential ligands of biogenic amine receptors. It was shown that mtoluoyl and m-toluenesulfonyl groups were preferred to obtain ligands with high affinity for 5-HT 7 , D 3 , D 4 receptors [6,8]. Modifications in three-and four-methylene group alkyl chains influenced 5-HT 1A -and 5-HT 2A -receptor affinity and selectivity [14]; finally, tetrahydroisoquinoline or 2-methoxyphenylpiperazine turned out to be probably the most prevalent core structures in CNS agents.…”