1.N6-cyclohexyladenosine, L-and D-N6-( phenylisopropyl)adenosine, N6-benzyladenosine, N6-phenyladenosine, adenosine 5'-cyclopropyl( ethyl)carboxainide, 2',5'-dideoxyadenosine, 5'-(methylthio)adenosine, 8-bromoadenosine, inosine, adenine.alkylxanthines: Profile with 8-phenyltheophylline, 1,3-dipropylxanthine, 3-isobutyl-l-inethylxanthine, theophylline, caffeine, 1,7-dirnethylxanthine, theobromine, isocaffeine.Structure-activity correlations for responses to ATP analogues: Profile with ATP, 2-Cl-ATP, 8-Br-ATP, 2'-(MeS)-ATP, ITP, GTP. Alteration in function by exogenous adenosine deaminase : Reduction in adenosine-mediated but not ATPmediated response. Alteration in function or responses by inhibition of adenosine deaminase: Potentiation of effects of endogenous adenosine by 2'-deoxycoformycin o r erythro-9-( 2-hydroxy-3-nony1)adenine. Alteration in function or responses by inhibitors of ecto-ATPases and nucleotidases: Blockade of conversion of ATP to adenosine with a,P-methyleneadenosine diphosphate.Alteration in function or responses by inhibitors of adenosine uptake: Potentiation of adenosine-mediated but not ATP-mediated responses by dipyridamole, dilazep, hexobendine, 6-@-nitrobenzyl)thioguanosine, papaverine.Reduction of intracellular adenosine levels with homocysteine.binding of [3H]adenosine analogues and PHIalkylxanthines with physiological or biochemical responses.Structure-activity correlations for responses to adenosine analogues: Profile with adenosine, 2-chloroadenosine, 2.Structure-activity correlations for alteration in physiological function or in blockade of adenosine responses by 3. 4. .6. 7.8. 9.Control of intracellular levels of adenosine due to action of S-adenosylhomocysteine :Characterization of membrane receptors with radioactive ligands. Comparison of structure-activity for See text for discussion.

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An attempt to develop a highly cardioselective beta-adrenoceptor antagonist devoid of intrinsic sympathomimetic activity (ISA) focused on exploring structure-activity relationships around (S)-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy] phenyl]-4-(2-thienyl)imidazole. Strategies to reduce or eliminate ISA centered on structural changes that could influence activation of the receptor by the drug itself or by a metabolite. The approaches involved (a) eliminating the acidic imidazole N-H proton, (b) incorporating substituents ortho to the beta-adrenergic blocking side chain, (c) increasing steric bulk around the N-H moiety, (d) decreasing lipophilicity, (e) introducing intramolecular hydrogen bonding involving the imidazole N-H, and (f) displacing the imidazole ring from an activating position by the incorporation of a spacer element. The compounds were investigated in vitro for beta-adrenoceptor antagonism and in vivo for ISA. From these studies, the most successful variation involved the insertion of a spacer between the imidazole and aryl rings. (S)-4-Acetyl-2-[[4-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]methyl] imidazole (S-51) was demonstrated to be highly cardioselective (dose ratio beta 2/beta 1 greater than 9333) and devoid of ISA.