Cholinergic false transmitters: Physiological and biochemical actions in central and peripheral systems

Abstract

Three N-ethyl substituted analogs of acetylcholine (ACh) were evaluated for potential use as false neurotransmitters to decrease cholinergic transmission. This evaluation included (1) the elevation of arterial blood pressure upon central administration, (2) depression of blood pressure upon intravenous injection and (3) interactions with central muscarinic and peripheral nicotinic receptors. With respect to the central presser response, ACh, acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) were full agonists of decreasing potency; acetyltriethylcholine (ATECh) was a partial agonist of considerably lower potency. The duration of response paralleled potency. With respect to the peripheral depressor response, ACh and AMECh were full agonists of equal potency, and ADECh and ATECh were partial agonists of at least 100-fold lower potency. In terms of their affinity for central muscarinic receptors (brainstem and cerebral cortex), the following series was obtained: ACh > AMECh > ADECh = ATECh. All of the agents had a greater affinity for muscarinic receptors in the brainstem compared to cortex. Acetylcholine and AMECh recognized multiple receptor binding conformations; the binding of ADECh and ATECh indicated interaction with a single set of equivalent sites. The affinity for nicotinic ACh receptors from the Torpedo electric organ was ACh = AMECh > ADECh; ATECh had little affinity for these receptors. Acetylcholine, AMECh and ADECh stimulated the binding of [ 3H]phencyclidine to the ion channel of nicotinic receptor (potency series = ACh > AMECh = ADECh); ATECh was inactive. Acetylcholine, AMECh and ADECh also induced receptor conversion to a desensitized conformation; ATECh did not. These findings suggest (1) that AMECh would be ineffective as an inhibitory false transmitter because it possessed almost the same affinity and intrinsic activity as ACh and (2) that ADECh and ATECh, if released from nerve terminals in the same quantities as ACh, would produce the greatest functional hypocholinergic state.