A novel synthesis of xanthines: support for a new binding mode for xanthines with respect to adenosine at adenosine receptors

Non‐Xanthine Antagonists for the Adenosine A1 Receptor

“…In this paper, the His 7.43 residue was proposed to be of great importance for agonist binding to the receptor, confirming earlier biological data [42]. In a return to the ligand-based approach, Doytchinova and Petrova [43] proposed a refinement of the −N 6 ÀC(8)× model as proposed by Peet et al in 1990 [44]. The −N 6 ÀN(7)× model suggested that a slight shift in the superimposition of the xanthine and the agonist would give a better electrostatic and steric −fit×.…”

Bioisosterism, enantioselectivity, and molecular modeling of new effective N6‐ and/or N(9)‐substituted 2‐phenyl adenines and 8‐aza analogs: Different binding modes to A1 adenosine receptors

“…Among them, the most stereoselective compounds were 9-(1-phenyl)ethyl-2-phenyl-7,8-dimethyl-7-deazaadenine (ADPEP), ER = 35, [Muller et al, 1990] and 1-phenyl-ethyl-2-phenyl-4-aminopyrimido [4,5-b]indole (DPEAP), ER = 96 [Muller et al, 1996]. The enantioselectivity was attributed to the pocket facing the N 6 of adenosine also for these antagonists [Muller et al, 1996;Peet et al, 1990]. In these studies it was also evidenced, with regard to the group in the 2-position, that unsubstituted phenyl conferred the best affinity to the molecules; analogous results had previously been obtained on 2-aryl-8-azaadenines [Biagi et al, 1991].…”

“…In fact, not only A 1 adenosine receptor agonists bind to receptors in a stereoselective manner, for example, the eudismic ratio (ER = K i of S / K i of R enantiomer) between R-PIA [R-N 6 -1-methyl-2-phenylethyl-adenosine] and S-PIA was ca. 50 [Schwabe and Trost 1980]; but also among antagonists some stereoselective compounds were obtained such as R-1, 3-dipropyl-8-(1-methyl-2-phenylethyl)-xanthine, which was 9-fold more potent than its S-enantiomer [Peet et al, 1990]. Also, 9-substituted adenines having an asymmetric center in the N 6 -substituent showed moderate stereoselectivity [Thomson et al, 1991].…”

Electronic structure of some adenosine receptor antagonists: I. Equilibrium geometries, charge density distributions, and substituent effects

“…In a computer model published by Peet et al [3], the so called N 6 -C8 model, the authors described a binding mode for xanthines with respect to adenosines in which the N 6 -substituent of adenosine and the 8-substituent of adenosine and the 8-substituent of xanthines are overlapping. As a consequence the N1 nitrogen of adenosines and xanthines coincide.…”

“…As a consequence, the five-membered ring shows a high degree of coplanarity; in fact, all except N7 are coplanar. The N7 shows in principle an sp 3 state of hybridization yet the deformation of the C5ON7OC8 angle indicates a fractional order less than 3 for this hybridization. On the other hand, the two nitrogen atoms in the six-membered ring show almost essential sp 3 character, thus disturbing the coplanarity of the ring considerably (cf .…”