Allosteric Interactions of Quaternary Strychnine and Brucine Derivatives with Muscarinic Acetylcholine Receptors

• Published in: Journal of medicinal chemistry 1999-02, Vol.42 (3), p.438-445
• Main Authors: Gharagozloo, Parviz, Lazareno, Sebastian, Popham, Angela, Birdsall, Nigel J. M
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Animals; Biological and medical sciences; CHO Cells; Cholinergic system; Cricetinae; Humans; Medical sciences; Muscarinic Antagonists - pharmacology; N-Methylscopolamine - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Receptors, Muscarinic - metabolism; Structure-Activity Relationship; Strychnine - analogs & derivatives; Strychnine - chemistry; Strychnine - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970799y

The affinity and allosteric properties of 22 quaternary derivatives of strychnine and brucine at the m1−m4 subtypes of muscarinic receptors have been analyzed and compared. The subtype selectivity, in terms of affinity, was in 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 cooperative with the antagonist, N-methylscopolamine, at m2 receptors and, in the case of the strychnine analogues, were positively cooperative with N-methylscopolamine at least at one other subtype. The strychnine analogues were negatively cooperative with the neurotransmitter, acetylcholine, at all subtypes whereas brucine and five of the six derivatives examined were positively cooperative with acetylcholine at one or more subtypes (m1−m5) and exhibited different patterns of subtype selectivity. The ability to generate subtype-selective allosteric enhancers of acetylcholine binding and function may be of use in the development of drugs for the treatment of Alzheimer's disease.