Affinities of different cholinergic agonists for the high and low affinity states of hippocampal M1 muscarine receptors.

The ability of 16 well-known cholinergic agonists to compete with 1 nM [3H]pirenzepine for the high (KH) and low (KL) affinity states of M1 muscarine receptors was studied, using rabbit hippocampal membranes suspended in 20 mM Tris buffer containing 1 mM MnCl2, at pH 7.4 and 25 degrees C. The hippocampus, like the cerebral cortex, has primarily m1 and m3 subtypes of M1 receptors; these receptors have very similar affinities for pirenzepine and for agonists, and both receptors are coupled to the activation of phospholipase C. KH values varied more than 10,000-fold, and did not correlate with prior measurements of the ability of agonists to promote cerebral excitation or phosphoinositide turnover in cortical tissue. KL values varied more than 1,000-fold, and also did not correlate with agonist activities. In contrast, KL/KH ratios for individual agonists varied from 66 for cis-dioxolane to near 1 for oxotremorine, and correlated closely with data concerning the relative physiological and biochemical effectiveness of the agonists. Each agonist showed only a single affinity in 0.2 mM guanyl-5'-yl imidodiphosphate. Thus binding measurements of KL/KH appear to be a new way to screen cholinergic agonists for relative efficacy at m1 or m3 receptors coupled to their native G proteins. Whereas both quaternary and tertiary agonists are known to activate M2 receptors, only the quaternary agents tested were highly effective M1 agonists. The five agonists which have been tested for improving human memory all appear to have low efficacy at M1 receptors.