A. P. Ijzerman

Purine-Substituted Adenosine Derivatives with Small N6-Substituents as Adenosine Receptor Agonists

Abstract Adenosine, 6-hydroxylaminopurineriboside (HAPR), N6-methyl-adenosine and various derivatives of which the synthesis is described, were evaluated as adenosine receptor ligands in radioligand binding studies to probe the relative importance for affinity of small N6-substituents. The findings were incorporated in a recently developed three-dimensional model for the adenosine A, receptor, rationalising the more or less equal contribution to affinity of such different substituents as -OH and -CH3.

Partial agonists for adenosine receptors

Publisher Summary This chapter discusses the partial agonists for adenosine receptors. Adenosine is generally considered as a “local hormone” with profound physiological activity. It is thought to mediate a large variety of effects, as diverse as vasodilation in the cardiovascular system, inhibition of lipolysis in fat cells, and depression of neuronal activity in the central nervous system (CNS). Most of its effects are mediated by membrane-bound receptors, called P i -purinoceptors, of which currently three subclasses are defined: A l , A 2 and A 3 . All three classes have been cloned, and are coupled to the enzyme adenylate cyclase, A 1 and A 3 adenosine receptors in an inhibitory, and A 2 receptors, of which two further subtypes A 2a and A 2b exist, in a stimulatory fashion. The chapter discusses some methods for screening partial agonists as well as application of these screening methods to adenosine receptors. There is also a description of how partial agonists for adenosine receptors were obtained for the purpose of this chapter. In view of the overwhelming number of therapeutic strategies already in clinical practice, the hypotensive effects of adenosine receptor agonists are probably of limited use. On the contrary, the potentially beneficial metabolic, antiarrhythmic, and CNS effects elicited by these compounds are confounded by the cardiovascular actions.

Synthesis of 1,5-Anhydro-2-(N 6-Cyclopentyladenin-9-Yl)-2-Deoxy-D-Altrohexitol

Abstract The N 6-cyclopentyladenosine (CPA) analogue (4) was synthesized in 10 steps starting from glucose. The results of the radioligand binding assays are consistent with the thus far published findings that compounds containing a six-membered moiety at N 9 exhibit extremely weak affinity for adenosine receptors. Replacement of the ribofuranosyl moiety of CPA (2) by a 2-deoxy-D-altrohexitol moiety is sufficient to completely abolish its agonist activity.

Synthesis of 3′-Fluoro-3′-deoxy-N6-cyclopentyladenosine

Abstract Starting from 9-(β-D-xylofuranosyl)-6-chloropurine, the title compound was prepared in four steps. Reaction with cyclopentylamine followed by treatment of the 2′-O,5′-O-ditritylated material with diethylaminosulfur trifluoride (DAST), yielded after deprotection the desired compound.

Mapping the Xanthine CS-Region of the Adenosine A, Receptor with Computer Graphics

Substitution at the 8-position of 1,3-dipropylxanthines can lead to very potent and selective adenosine A1 antagonists. The xanthine C8-region was investigated in this study, using CAMM (computer-assisted molecular modeling). This region can be divided into two subregions with a considerable overlap in volume: a phenyl region which binds the flat substituents and a cycloalkyl region which binds the other substituents. The 8-phenyl-substituted derivatives bind with an N9-C8-Cl-C2 dihedral angle of 220 degrees; this dihedral angle is 330 degrees for the 8-cycloalkyl-substituted derivatives. The lower affinity of C8-substituted 7-methyl-1,3-dipropylxanthines can be explained quantitatively with steric hindrance, which C8-substituents experience from the 7-methyl group in these conformations. The substitution pattern determines the affinity for 8-phenyl-substituted compounds for which the energy cost to reach the dihedral angle of 220 degrees is low, but has little influence otherwise. The affinity of the 8-cycloalkyl-1,3-dipropylxanthines is mainly volume dependent, because of a forbidden area near the cycloalkyl region.

Recognition of Adenosine Receptors by Amiloride and Its Analogues

Abstract Amiloride and its analogues displace the adenosine A, receptor ligands [3H]CPDPX and [3H]PIA from their binding sites in calf brain membranes in a GTP-insensitive manner. High [NaCl] or low pH reduces the affinity of amiloride for A, receptors, whereas the affinity of [3H]CPDPX is not affected. Notwithstanding this difference in modulation, the interaction between amiloride and A, receptors appears competitive in nature. The structure-affinity relationships differ from those for classic amiloride-sensitive Na transport systems, indicating that a coupling between the A, receptor and one of these systems is very unlikely. Amiloride and its analogues may reprcsent a novel class of A, receptor antagonists.