Cyclic carbamate analogues of pilocarpine.
A number of pilocarpine analogues containing the (S)-3-ethyl-4-[(4'-imidazolyl)methyl]-2-oxazolidinone (9) structural feature were synthesized from L-histidine. With 1-benzyl-L-histidine as the key intermediate, a regiospecific synthetic route was developed to the N pi-methyl derivative 8. The regiochemistry of the alkylation of the imidazole nucleus was determined by measuring proton cross-ring coupling constants in the high-field 1H NMR. The effects on muscarinic receptors of these variously alkylated derivatives 6-10 were studied on isolated guinea pig ileum. The derivatives in which the imidazole nitrogen was unsubstituted (9), N tau-methylated (10), and N pi-methylated (8) were cholinergic muscarinic agonists with an increasing order of potency; compounds 6 and 7 were inactive. Analogue 8 with the same substitution pattern as pilocarpine was equipotent with pilocarpine, making these hydrolytically stable carbamate derivatives potentially useful drugs.
Sauerberg
P
P
Department of Chemistry, University of California, Berkeley 94720.
Chen
J
J
WoldeMussie
E
E
Rapoport
H
H
D000818:Animals; D001681:Biological Assay; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D003500:Cyclization; D006168:Guinea Pigs; D006639:Histidine; D007082:Ileum / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D010862:Pilocarpine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D002219:Carbamates; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D006639:Histidine