New developments in A1 and A2 adenosine receptor antagonists

The aim of this article is to briefly present progress in the development of the potent adenosine receptor (AR) antagonists with high selectivity for either A1, A2A, or A2B ARs. The structural requirements for each AR subtype were discussed as well as their potential therapeutic use. In the search for new AR antagonists, series of imidazo-, pyrimido-, and diazepino-purindione derivatives as well as oxazolo-, oxazino-, and oxazepino-purindiones were designed, synthesized, and preliminarily evaluated in pharmacological studies. Oxygencontaining tricyclic derivatives were shown to be moderately potent AR antagonists exhibiting selectivity either for A1 or A2A ARs. Tricyclic purindiones with nitrogen in the third ring were generally more A2A AR selective. The compounds tested in vivo according to the Antiepileptic Drug Development Program of the National Institutes of Health (USA) were generally active as anticonvulsants in chemically induced seizures. The endogenous nucleoside adenosine is an autacoid produced in many organs and tissues, exhibiting diverse potent physiological actions in the cardiovascular, nervous, pulmonary, renal, and immune systems. Extracellular adenosine either released from cells or ATP hydrolysis regulates several physiological functions by activation on specific cell membrane receptors. The combination of pharmacological studies and molecular cloning revealed the existence of four distinct adenosine receptor (AR) subtypes, which are identified and classified as A1, A2A, A2B, and A3, all belonging to the G protein-coupled, 7-transmembrane-segment receptors superfamily. Whereas the adenosine A1 and A3 receptor subtypes are coupled to the Gi protein, inhibiting adenylate cyclase, A2A and A2B subtypes stimulate this enzyme via Gs. A1 and A3 ARs may also be coupled to other second messenger systems, such as activation of phospholipase C (PLC), and A1 ARs can also lead to a stimulation of K + channels or an inhibition of Ca2+ channels [1]. Moreover, ARs are involved in interactions with receptors for other neurotransmitters and/or neuromodulators, namely receptors for neuropeptides (CGRP and VIP), ionotropic (NMDA) and *Plenary lecture presented at the Hungarian–German–Italian–Polish Joint Meeting on Medicinal Chemistry, Budapest, Hungary, 2–6 September 2001. Other presentations are published in this issue, pp. 1387–1509. †Corresponding author metabotropic (mGlu I and III) glutamate receptors, GABA and nicotinic autofacilitatory, muscarinic, and dopamine receptors [2–4]. ARs have been cloned from several mammalian species [1], including humans (human recombinant ARs were expressed in mammalian cell lines—CHO, HEK [5–7]). It was found that, for example, the human A1 AR differs by 18 amino acids from the dog A1 sequence and 16 amino acids from the rat A1 sequence, the human A2A AR differs by 28 amino acids from the dog A2A sequence [7]. ARs have become important targets for drug development. Selective interaction with AR subtypes offers very broad therapeutic potentials, including the regulation of the electrophysiological properties of the heart, kidney functions, immune system (including inflammatory activity), some central nervous system functions, and cell growth [8–12]. The main interest of this work concerns current developments of selective A1 and A2 AR antagonists. The A1 AR is found in high density in the brain (cortex, hippocampus) and in lower density in peripheral organs and tissues such as heart, kidney, lung, and fat cells. Adenosine A1 antagonists have the main therapeutic potentials as kidney-protective diuretics and agents for the treatment of dementias, including Alzheimer’s disease, depression, cardiac failure, and asthma [9,13]. During the past 20 years, a large number of A1 AR antagonists have been developed including bior tricyclic heterocyclic derivatives [13–15]. Important classes of A1-selective antagonists comprise xanthine derivatives with bulky 8-substituents, adenine derivatives with bulky N6-substituents, 7-deaza and 7-deaza-8-aza analogs of adenine, pyrazolo[1,5-a]pyridines, and other heterocyclic compounds (Fig. 1). K. KIEC-KONONOWICZ et al. © 2001 IUPAC, Pure and Applied Chemistry 73, 1411–142