5'-substituted adenosine analogs as new high-affinity partial agonists for the adenosine A1 receptor.

5'-(Alkylthio)-, 5'-(methylseleno)-, and 5'-(alkylamino)-substituted analogues of N6-cyclopen-tyladenosine (CPA) were synthesized in 30-50% overall yields. The affinities of these compounds for the adenosine A1 and A2A receptors were determined in rat brain membranes. The 5'-substituted CPA analogues proved selective for the adenosine A1 receptors, displaying affinities in the nanomolar range. The compounds were also evaluated for their ability to stimulate [35S]GTP gamma S binding, also in rat brain membranes. The Ki values in receptor binding studies corresponded well to the EC50 values thus obtained. Intrinsic activities of the compounds were tested in vitro by determining the GTP shift in receptor binding studies as well as the maximal binding of [35S]GTP gamma S. It appeared that the 5'-thio and 5'-seleno derivatives in particular behaved as partial agonists.

Synthesis and pharmacological investigation of new chiral muscarinic antagonists.

The two pairs of enantiomers of isoxazolidin-3-ones 3 and 4 were synthesized by means of Lipase PS-catalyzed hydrolyses of suitable racemic butyrates. The same butyrates were also employed as key intermediates in the preparation of racemic 3 and 4. The antimuscarinic potency of the new compounds was assayed in two in vitro functional tests. The eutomers (-)-3 and (-)-4 share the same stereochemistry (5R) of the most potent enantiomer of "azamuscarone" 2, a structurally related muscarinic agonist. Such a spatial arrangement around the chiral center of 2-4, coupled with the low values of eudismic ratio, represents an anomaly among the chiral muscarinic ligands. This anomaly was accounted for by the absence of a chiral center at C-2, a position whose configuration is crucial in determining the high enantioselectivity of muscarinic agonists and antagonists.