Survey of Nonxanthine Derivatives as Adenosine Receptor Ligands

Abstract

The binding affinities at rat A 1 , A 2a , and A 3 adenosine receptors of a wide range of heterocyclic derivatives have been determined. Mono-, bi-, tricyclic and macrocyclic compounds were screened in binding assays, using either [ 3 H]PIA or [ 3 H]CGS 21680 in rat brain membranes or [ 125 I]AB-MECA in CHO cells stably transfected with rat A 3 receptors. Several new classes of adenosine antagonists (e.g. 5-oxoimidazopyrimidines and a pyrazoloquinazoline) were identified. Various sulfonylpiperazines, 11-hydroxytetrahydrocarbazolenine, 4H-pyrido[1,2-a]pyrimidinone, folic acid, and cytochalasin H and J bound to A 3 receptors selectively. Moreover, cytochalasin A, which bound to A 1 adenosine receptors with K i value of 1.9 μM, inhibited adenylyl cyclase in rat adipocytes, but not via reversible A 1 receptor binding.

Non‐Xanthine Antagonists for the Adenosine A1 Receptor

“…It was reasoned that replacement of this group with rigid heteroaromatics would retain the affinity of FK 453 (13) whilst preventing isomerization of the CC bond. This led to the discovery of a highly potent 2-substituted-2,3-dihydro-3-oxopyridazin-6-yl group (which incidentally was a fragment of one of the compounds screened by Siddiqi et al in 1996 that showed some affinity for the adenosine receptors [61]) (14 ± 24; Fig. 5).…”

“…9 and Table 10) only yielded mm affinities with not much selectivity over the A 2(A) receptors. Siddiqi et al screened many compounds and found some affinity for naphthyridine derivatives [61]. More recently, Ferrarini et al published more lucrative substitution about the 1,8-naphthyridine ring [119].…”

“…In 1985, a selection of barbiturates (pyrimidine-2,4,6-triones) were investigated at the A 1 adenosine receptor [60] and, although reportedly selective antagonists of the A 1 receptor, they only showed affinity in the mm range. A screening by Siddiqi et al [61] showed two pyridine derivatives to have mm affinity at the A 1 receptor with slightly more affinity for the A 3 receptor. In 1997, Biagi et al [62] compared analogous pyrimidines to their 8-azaadenine series and found them to be of much lower activity, and thus concluded that the bicyclic aromatic system was necessary for good affinity at the adenosine A 1 receptor.…”

Die adenosien A₁- en A_2A-reseptoraffiniteit van ’n reeks 3,4-dihidropirimidoon-analoë

“…Die 3,4-dihidropirimidoon-analoë se adenosien A 2A -affiniteit kan moontlik verhoog word deur die dihidropirimidoonring te vervang met 'n planêre aromatiese pirimidienring wat π-π-stapelingsinteraksies met Phe-168 kan ondergaan. 'n Soortgelyke tendens is ook waargeneem waar 'n planêre konformasie deur nie-xantienderivate verbeterde adenosien A 1 -affiniteit opgelewer het, maar geen verbetering in adenosien A 2A -affiniteit bewerkstellig het nie (Siddiqi et al 1996).…”

The utilization of a unified pharmacophore query in the discovery of new antagonists of the adenosine receptor family

“…2 Novel adenosine receptor ligands, including flavonoids, dihydropyridines, tetrahydrobenzo-thiophenones, isoquinolines, and a triazolonaphthyridine and thiazolo-pyrimidine have been identified through the screening of chemical libraries of natural products and various heterocyclic derivatives. [3][4][5] A unified pharmacophore model based on steric and electrostatic fit of various A 3 receptor antagonists has recently been reported by Moro et al (1998). 6 Adenosine receptor antagonists having selectivity for A 1 and A 2 A receptors have been under development as anti-arhythmic, 7 renoprotective, 8 anti-Parkinson's, 9 anti-depressant, 10 and cognition enhancing 11 drugs.…”