STEREOSELECTIVE INTERACTION OF UNCHARGED ESTERS AT 4 MUSCARINIC RECEPTOR SUBTYPES

We investigated the binding and pharmacological properties of the este rs of 3,3-dimethylbutan-1-ol (the carbon analogue of choline) with eit her diphenylglycolic acid, (R)-phenylcyclohexylglycolic acid, or (S)-p henylcyclohexylglycolic acid [BS-6181, (R)-BS-7826 and (S)-BS-7826, re spectively] at muscarinic M(1), M(2), M(3) (Hm3) and M(4) receptors. T he three uncharged compounds were muscarinic receptor antagonists, wit h pA(2) or pK(i) values between 7.9 and 5.6. The achiral ester BS-6181 displayed highest affinity for M(1), M(3) (Hm3) and M(4) receptors (p A(2) or pK(i) = 7.2-7.6) and lower affinity for M(2) receptors (pA(2) or pK(i) = 6.7 and 6.8). The four muscarinic receptor subtypes were ab le to distinguish between the two enantiomers of the cyclohexyl deriva tive of BS-6181 [(R)- acid (S)-BS-7826], with a preference for the (R) -isomer (up to 79-fold). Interestingly, the (S)-enantiomer of BS-7826, being the distomer, was found to be M(4) selective (pK(i)/M(4) = 6.9; pA(2) or pK(i)/M(1)-M(3) (Hm3) = 5.6-6.2). These results indicate tha t uncharged compounds may (stereo)selectively bind to muscarinic recep tors via hydrophobic interactions. Thus, an ionic bond between muscari nic ligands and an anionic site of the receptor is not absolutely nece ssary for recognition of muscarinic receptors.