Muscarinic acetylcholine receptors are membrane receptors involved in many physiological processes. Malfunction of muscarinic signaling is a cause of various internal diseases, as well as psychiatric and neurologic conditions. Cholesterol, neurosteroids, neuroactive steroids, and steroid hormones are molecules of steroid origin that, besides having well-known genomic effects, also modulate membrane proteins including muscarinic acetylcholine receptors. Here, we review current knowledge on the allosteric modulation of muscarinic receptors by these steroids. We give a perspective on the research on the non-genomic effects of steroidal compounds on muscarinic receptors and drug development, with an aim to ultimately exploit such knowledge.

• Keywords
• allosteric modulation, cholesterol, muscarinic receptors, neuroactive steroids, neurosteroids,
• MeSH
• Cholesterol MeSH
• Hormones metabolism   MeSH
• Neurosteroids * pharmacology   MeSH
• Receptors, Muscarinic MeSH
• Steroids pharmacology   MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Cholesterol MeSH
• Hormones MeSH
• Neurosteroids * MeSH
• Receptors, Muscarinic MeSH
• Steroids MeSH

Allosteric enhancement of the affinity of muscarinic receptors for their ligands offers a new way to influence cholinergic neurotransmission. The structure of the allosteric binding domain(s) and the features of agonists, antagonists and modulators which determine the occurrence of either positive or negative cooperativity require clarification. We tested interactions between allosteric modulators alcuronium, strychnine and brucine and eight antagonists at muscarinic receptors expressed in CHO cells. In experiments with unlabeled antagonists, all three modulators enhanced the affinity for 4-diphenylacetoxy-N-dimethylpiperidinium (4-DAMP) at the M2 receptors, and strychnine did so also at the M4 receptors. Positive interactions were also observed between alcuronium and L-hyoscyamine (M2) and scopolamine (M2), between strychnine and butylscopolamine (M4), L-hyoscyamine (M2 and M4) and scopolamine (M4), and between brucine and scopolamine (M2). Positive effects of alcuronium, strychnine and brucine on the affinity of the M2 receptors for 4-DAMP have been confirmed by direct measurements of the binding of [3H]-4-DAMP. A comparison of molecular models of several antagonists which are esters revealed that antagonists in which the distance between the N and the carboxyl C atoms corresponds to five chemical bonds are more likely to display positive cooperativity with alcuronium at the M2 receptors than the antagonists in which the N-carboxyl C distance corresponds to four chemical bonds.

• MeSH
• Alcuronium pharmacology   MeSH
• Allosteric Regulation MeSH
• Muscarinic Antagonists chemistry   pharmacology   MeSH
• CHO Cells MeSH
• Cricetinae MeSH
• N-Methylscopolamine metabolism   MeSH
• Piperidines pharmacology   MeSH
• Radioligand Assay MeSH
• Strychnine analogs & derivatives   pharmacology   MeSH
• Tritium MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 4-diphenylacetoxy-1,1-dimethylpiperidinium MeSH Browser
• Alcuronium MeSH
• Muscarinic Antagonists MeSH
• brucine MeSH Browser
• N-Methylscopolamine MeSH
• Piperidines MeSH
• Strychnine MeSH
• Tritium MeSH