Allosteric interactions of quaternary strychnine and brucine derivatives with muscarinic acetylcholine receptors

The affinity and allosteric properties of 22 quaternary derivatives of stry chnine and brucine at the m1-m4 subtypes of muscarinic receptors have been analyzed and compared. The subtype selectivity, in terms of affinity, was i n general m2 > m4 > m1 > m3. The highest affinities were found for N-benzyl , N-2-naphthylmethyl, and N-4-biphenylylmethyl strychnine (13, 14, and 18, respectively). All the strychnine and brucine derivatives were positively c ooperative with the antagonist, N-methylscopolamine, at m2 receptors and, i n the case of the strychnine analogues, were positively cooperative with N- methylscopolamine at least-atone other subtype. The strychnine analogues we re negatively cooperative with the neurotransmitter, acetylcholine, at all subtypes whereas brucine and five of the six derivatives examined were posi tively cooperative with acetylcholine at one or more subtypes (m1-m5) and e xhibited different patterns of subtype selectivity. The ability to generate subtype-selective allosteric enhancers of acetylcholine binding and functi on may be of use in the development of drugs for the treatment of Alzheimer 's disease.