Adenine derivatives substituted in position 9 constitute an important class of pharmacologically active compounds for which different targets can be postulated. Because they resemble the structure of adenosine, they may compete with the neuromodulator at its specific pharmacological receptors,1 transport proteins, or metabolic enzymes. Particularly erythro-9-(2-hydroxy-3nonyl)adenine (EHNA) is known as a potent inhibitor of adenosine deaminase2 (Figure 1). However, 9-substituted adenines also constitute possible competitors for adenosine-deriving endogenous substances, such as adenosine monophosphate and its corresponding cyclic nucleotide, diphosphate, and triphosphate (AMP, cAMP, ADP, ATP) respectively. Thus EHNA was found to inhibit a specific phosphodiesterase (PDE) isozyme found in heart3 and vascular endothelial cells4 with micromolar IC50 values. Several years ago, Kelley et al. described a 9-benzyladenine derivative (BWA78U) possessing potent anticonvulsant effects.5 As this compound also presents potent anxiolytic and sedative properties,6 an interaction with benzodiazepine receptors has been first suspected, but found to be very weak7,8 ([3H]diazepam, IC50 ) 13 μM). Moreover, a pretreatment of the rats with the benzodiazepine receptor antagonist flumazenil did not block the potent anticonvulsant properties of this compound (Marescaux and Bourguignon, unpublished results). As BWA78U did not bind to A1 and A2 adenosine receptors ([3H]CHA and [3H]NECA, IC50 > 100 μM), we evaluated its capacity to inhibit the different phosphodiesterases (PDE), particularly those hydrolyzing cAMP. Following the classification proposed by Beavo,9 the different PDE isoforms can be grouped into seven families according to the related gene, their substrate specificity, their modulation by endogenous regulators (calcium-calmodulin, cGMP), and their selective inhibitions by typical inhibitors. In this paper, we report the behavior of BWA78U and some of its analogues toward PDE3 and PDE4 preparations. It appears that some of these compounds exhibit potent phosphodiesterase inhibition properties with high selectivity toward PDE4. Chemistry. The 2-substituted 6-chloropurines 2a-c were obtained from their corresponding hypoxanthines10-12 by treatment with POCl3 in presence of N,N-dimethylaniline (Scheme 1).13 Deprotonation of 6-chloropurines 2 by means of potassium carbonate in DMF or DMSO, and subsequent alkylation with different akyl halides, afforded the corresponding 9-substituted isomers 3 as major compounds. The 6-chloro-4,5diaminopyrimidines 4, obtained as described earlier,5 were reacted with methyl orthoacetate in presence of catalytic amounts of methanesulfonic acid to yield the corresponding 8-methylchloropurines 5. Treatment of the latter compounds 3 or 5 with various amines provided the desired adenines 6 (NCS compounds). The most basic adenines were analyzed and tested as their hydrochlorides or their more water-soluble methanesulfonate salts. The efficiencies of a first series of differently substituted 9-alkyladenines have been evaluated as PDE inhibitors via their IC50 values on PDE3 and PDE4 from vascular smooth muscle. The concentration of each drug that inhibited 50% of the enzymatic activity was determined at 1 μM substrate concentration. Data are listed in Table 1.