Conformational Restriction in Novel NAN‐190 and MP3022 Analogs and Their 5‐HT_1A Receptor Activity

Abstract

The newly synthesized analogs of NAN-190 containing m-Cl and m-CF(3) substituents in the arylpiperazine moiety and their conformationally restricted counterparts showed a very high 5-HT(1A )receptor affinity. In the LLR test, the flexible compounds 4a and 5a displayed features of a partial agonist and agonist, respectively. The conformational restriction in the tested structures caused alternations in the observed in vivo effects; compounds 4b and 5b were classified as an inactive agent and an antagonist of postsynaptic 5-HT(1A )receptors, respectively. Rigidification of MP3022 and its 5,6-dimethyl analog structures resulted in cis and trans stereoisomers 6b-9b with a 1- and 2-substituted benzotriazole moiety. In both series, in vitro experiments showed that the cis configurations of the compounds were better tolerated by 5-HT(1A) receptor sites than the trans ones. The conformational analysis revealed various spatial regions that can be explored by terminal benzotriazole fragments in those structures. Like the previously described cis-6b, the new ligand cis-7b, displayed features of a postsynaptic 5-HT(1A) receptor agonist, whereas cis-8b was characterized as a partial agonist of those receptor sites. It was suggested that the nonlinear geometry of the above agents has significant influence on the postsynaptic 5-HT(1A )receptor stimulation.

Catalyst-Free Regioselective N2 Arylation of 1,2,3-Triazoles Using Diaryl Iodonium Salts

“…Since then, many practical methods have been developed for the postmodification of 1,2,3-triazoles to provide N 1 -substituted 1,2,3-triazoles . On the contrary, only a few synthetic methods have been reported to access N 2 -substituted 1,2,3-triazoles − despite their promising biological activities. − N 2 -Aryl-1,2,3-triazole-containing molecules display interesting biological activities. For example, they have been used in a potent dual orexin receptor antagonist for the treatment of primary insomnia .…”

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry

“…Replacement of a spirocyclopentane moiety at the C4-position of the piperidinedione scaffold in 99 with a gem-dimethyl group yielded 98, which had a higher affinity for the 5-HT 1A receptor 100 compared to the 5-HT 2A receptor 101 and D 2 receptor. 102 The binding affinity (K i ) of 99 for the 5-HT 1A , 5-HT 2A , and D 2 receptors is shown in Figure 29. 103 Human Renin Inhibitor 102 (Aliskiren/Tekturna).…”

Zastosowanie Metod Obliczeniowych Do Wyznaczania Budowy Modeli Farmakoforowych Receptorów 5-Ht1a, 5-Ht2a Oraz 5-Ht7

“…W ostatnich latach ukazało się wiele prac poświęconych aktywności farmakologicznej tej grupy związków. Intensywne badania zależności struktura-aktywność dowodzą, że aktywność jest wynikiem obecności grupy arylowej przy atomie N1 pierścienia piperazyny oraz łańcucha alkilowego [27,28,29] alkoksylowego [30,31], alkenylowego [32,33] lub układu cykloheksylowego przy N4 [34,35,36,37]. Niektórzy autorzy podkreślają również rolę końcowego hydrofobowego ugrupowania cyklicznego w stabilizacji kompleksu ligand-receptor poprzez oddziaływania π-π oraz dipolowe [23,37,38,39].…”