Cholinergic Agents: Effect of Methyl Substitution in a Series of Arecoline Derivatives on Binding to Muscarinic Acetylcholine Receptors

Synthesis and Modeling Studies of a Potent Conformationally Rigid Muscarinic Agonist: 1-Azabicyclo[2.2.1]heptanespirofuranone

“…Both compounds exhibited 100% inhibition on cAMP formation in guinea pig heart, an M2 functional assay 7c. The size limit for agonism for the quinuclidine ring vs 1-azabicyclo[2.2.1]heptane is very striking and quite different from that of the oxadiazole series reported by Saunders et al However, similar observations have been reported in the literature when there is an increase in size of a muscarinic agonist ) did not affect the Oxo-M affinity, the intrinsic activity was reduced drastically, showing the typical SAR trend for muscarinic agonists .…”

“…The size limit for agonism for the quinuclidine ring vs 1-azabicyclo[2.2.1]heptane is very striking and quite different from that of the oxadiazole series reported by Saunders et al However, similar observations have been reported in the literature when there is an increase in size of a muscarinic agonist ) did not affect the Oxo-M affinity, the intrinsic activity was reduced drastically, showing the typical SAR trend for muscarinic agonists . The affinity of four stereoisomers of the rigid dioxolane analogue 9 was reported to be in the range of 0.014−0.55 μM in the Oxo-M assay, which shows that they are much less active than 1a , albeit they are also rigid analogues.…”

Identification and Characterization of m1 Selective Muscarinic Receptor Antagonists

“…All examples shown in Table were prepared by the synthetic route illustrated in Scheme . Treatment of the protected nicotinic acid derivative, 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)pyridine ( II ), with phenyllithium yielded the 1,4-dihydrophenylpyridine intermediate III . Aromatization of III in the presence of sulfur yielded pyridine IV .…”

Muscarinic Receptor Agonists and Antagonists

“…The exquisite sensitivity to substitution may be judged from the monomethyl-derivatives ( 34 ) which were all antagonists-partial agonists. Even the ethyl derivative ( 33d ) is only a partial agonist [ 67 ] and N -desmethylarecoline (guvacoline) has a lower affinity for muscarinic receptors. The propargyl ester ( 33c ) is as potent as the methyl ester ( 33b ), and is frequently used as a research tool because it has slight M 2 selectivity, however it is too easily hydrolysed to be a viable medicine [ 68 ].…”