Muscarinic receptor subtype specificity of (N,N-dialkylamino)alkyl 2-cyclohexyl-2-phenylpropionates: cylexphenes (cyclohexyl-substituted aprophen analogues).
A series of aprophen [(N,N-diethylamino)ethyl 2,2-diphenylpropionate] analogues, called cylexphenes, were synthesized with alterations in (1) the chain length of the amine portion of the ester, (2) the alkyl groups on the amino alcohol, and (3) a cyclohexyl group replacing one of the phenyl rings. The antimuscarinic activities of these analogues were assessed in two pharmacological assays: the inhibition of acetylcholine-induced contraction of guinea pig ileum, and the blocking of carbachol-stimulated release of alpha-amylase from rat pancreatic acinar cells. These two tissues represent the M3(ileum) and M3(pancreas) muscarinic receptor subtypes. In addition, the analogues were also evaluated for their competitive inhibition of the binding of [3H]NMS to selected cell membranes, each containing only one of the m1, M2, m3, or M4 muscarinic receptor subtypes. The m1 and m3 receptors were stably transfected into A9 L cells. The replacement of one phenyl group of aprophen with a cyclohexyl group increased the selectivity of all the analogues for the pancreatic acinar muscarinic receptor subtype over the ileum subtype by more than 10-fold, with the (N,N-dimethylamino)propyl analogue exhibiting the greatest selectivity for the pancreas receptor subtype, over 30-fold. The cylexphenes also showed a decrease in potency in comparison to the parent compound when examined for the binding of [3H]NMS to the M2 subtype. In agreement with the pharmacological data obtained from the pancreas, the (N,N-dimethylamino)propyl cylexphene 3 demonstrated the greatest selectivity for the m3 subtype, and additionally showed a preference for the m1 and M4 receptor subtypes over the M2 receptor subtype in the binding assay. Thus, this compound showed a potent selectivity according to the pharmacological and binding assays between the muscarinic receptor subtypes of the pancreas and ileum. In both the pharmacological and binding assays, the potency of the analogues decreased markedly when the chain length and the bond distance between the carbonyl oxygen and protonated nitrogen were increased beyond three methylene groups. When the structures of these analogues were analyzed using a molecular modeling program, the bond distance between the carbonyl oxygen and protonated nitrogen was deduced to be more important for the antagonist activity than subtype specificity.
Leader
H
H
Division of Biochemistry, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Gordon
R K
RK
Baumgold
J
J
Boyd
V L
VL
Newman
A H
AH
Smejkal
R M
RM
Chiang
P K
PK
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002217:Carbachol / Q000494:pharmacology; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D009116:Muscarine / Q000037:antagonists & inhibitors*; D009119:Muscle Contraction / Q000187:drug effects; D019832:N-Methylscopolamine; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012602:Scopolamine Derivatives / Q000378:metabolism; D014162:Transfection; D000516:alpha-Amylases / Q000378:metabolism
D003510:Cyclohexanes; D010666:Phenylpropionates; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D009116:Muscarine; D002217:Carbachol; D000516:alpha-Amylases; D000109:Acetylcholine; C006615:aprofen; D019832:N-Methylscopolamine