Synthesis of cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines and their evaluation as 5-HT6 receptor antagonists

2-Substituted 5,6-dimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines: New series of highly potent and specific serotonin 5-HT6 receptor antagonists

“…Recently, we have reported [8,9] on the synthesis and biological activity of novel 5-HT 6 R antagonists, 3-phenylsulfonyl-cycloalkano [e and d]pyrazolo [1,5-a]pyrimidines I and II (Fig. 1), which posses both the picomolar range affinity and excellent selectivity profiles.…”

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

“…This is in accordance with a few reports which have proven that the presence of a basic nitrogen atom enabling formation of the interaction of its protonated form and D3.32 is not indispensable for the dopamine D 2 receptor anchoring (Xiao et al 2014;Kaczor et al 2016b). Non-basic ligands are also known for some other aminergic GPCRs, e.g., the serotonin 5-HT 6 receptor (Ivachtchenko et al 2010) and for opioid receptors, including κ opioid receptor ligand, salvinorin A and μ opioid receptor ligands, carbonyl derivatives of 1-aryl-2-iminoimidazolidine (Matosiuk et al 2001(Matosiuk et al , 2002aSztanke et al 2005).…”

Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists

“…Chemistry 2-Methylthio (9-12) and 2-methylamino (13)(14)(15) ARSPPs were obtained in the reaction of 3-amino-4-arylsulfonylpyrazoles 1-7 with 1,1,3,3-tetramethoxypropane 8 in acetic acid at 100°C (Scheme 1). 5,7-Dimethyl-2-methylthio ARSPPs 23-28 and (5,7-dimethyl-2-methylamino ARSPPs 29-33 were obtained in the reaction of corresponding 3-amino-4-arylsulfonylpirazoles 2-4, 6-7, and 16-21 with acetylacetone 22 in acetic acid (Scheme 2) in conditions similar to ones described earlier.…”

“…We have concluded that at least three factors could be responsible for the high potency of the compounds: (i) torsion angles between the phenylsulfonyl moiety relative to the heterocycle core plane, which define the conformation of the molecule, (ii) the nature and size of a substituent in the 2-position, 12 and (iii) the formation of an intramolecular hydrogen bond between the basic amino group located next to the sulfonyl group, which may stabilize an advantageous binding conformation. 14 In particular, we have shown [12][13][14] that in the corresponding pairs of potent and selective 2-methylamino-and methylthiosubstituted ARSPPs A, B and C, D (Fig. 1), the methylamino-substituted B and D, which can form intramolecular hydrogen bonds, exhibit substantially higher potencies as 5-HT 6 R antagonists.…”