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Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates.

Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates. I

A new series of N-substituted-3-[1-alkyl(aryl)-4-piperidyl]azetidin-2-ones 2a-j structurally related to the previously reported 2,7-diazaspiro[3.5]nonan-1-ones 1 have been synthesized and tested for their activity as muscarinic agents, both in vitro and in vivo. Preliminary pharmacological results showed that compounds 2 are devoid of significant cholinergic properties.

Application of the Corey-Fuchs reaction on Boc-prolinal, Boc-4-hydroxyprolinal, Bocpiperidinal and Boc-serinal derivatives to give chiral 2-pyrrolidinyl-, 2-piperidinyl- and 4-oxazolidinyl-acetylene derivatives provided rapid access to a number of differentially constrained oxotremorine analogues as muscarinic agents.

A new series of N-substituted-3-[1-alkyl(aryl)-4-piperidyl]azetidin-2-ones 2a-j structurally related to the previously reported 2,7-diazaspiro[3.5]nonan-1-ones 1 have been synthesized and tested for their activity as muscarinic agents, both in vitro and in vivo. Preliminary pharmacological results showed that compounds 2 are devoid of significant cholinergic properties.

Racemic N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM-5), a putative postsynaptic agonist and presynaptic antagonist at muscarinic receptors, was resolved into the enantiomers by a new method suitable for large scale preparation. The method involves a chemoselective N-debenzylation as the key step. The enantiomers of BM-5 were obtained after six separate steps in 25% overall yield. The ability of the enantiomers to release acetylcholine was evaluated in vivo by use of brain dialysis. (R)-BM-5 was the more potent enantiomer in this assay.

Application of the Corey-Fuchs reaction on Boc-prolinal, Boc-4-hydroxyprolinal, Bocpiperidinal and Boc-serinal derivatives to give chiral 2-pyrrolidinyl-, 2-piperidinyl- and 4-oxazolidinyl-acetylene derivatives provided rapid access to a number of differentially constrained oxotremorine analogues as muscarinic agents.

Recent advances in the understanding of human behaviors indicate that genetic factors often play a critical role in regulating variation in behavior. Special attention has been paid to abnormal behaviors ranging from psychopathology to drug, usually alcohol, dependence. This chapter summarizes the data that suggest that genetic factors regulate the nicotinic and muscarinic cholinergic systems. Studies that indicate that the use of tobacco products by humans is genetically regulated are discussed in detail, as are animal studies that indicate that genetically determined differences in several aspects of nicotine pharmacology exist. Special emphasis is placed on those animal studies that have identified biochemical processes that may play critical roles in regulating genetically influenced variation in nicotine’s actions. A more cursory discussion of the genetics of human affective disorders is followed by an equally cursory summation of the limited animal literature, which argues that genetically determined variation in muscarinic cholinergic systems exists.

In freely moving male Wistar rats the hippocampal EEG was recorded by using chemitrodes (combinations of guide cannulas with bipolar recording electrodes) chronically implanted into the dorsal hippocampus (CA1). The muscarinic agents oxotremorine and arecoline applied intrahippocampally caused a long-lasting increase in the amount of rhythmical slow wave activity (RSA) of the hippocampal EEG accompanied by a decrease of the dominating frequency. At the same time, the well-known relationship between defined behavioral states and EEG patterns was abolished. The effect of oxotremorine could be blocked by subsequent application of the muscarinic antagonist scopolamine. The results support the hypothesis that a non-rhythmic activation of hippocampal muscarinic receptors may result in the generation of RSA within the hippocampal formation.

In order to obtain information on the steric requirements of the active sites of drug receptors, it is a matter of considerable interest to elucidate the steric und thermodynamic parameters that enable pharmacological compounds to initiate a response at a particular receptor. Due to the considerable flexibility of most of the drug molecules these aspects have to be studied indirectly by investigations of relationships between structure, stereochemistry and pharmacological activity of rigid or semirigid model compounds. It is the aim cf this review to discuss the advantages and also the disadvantages and limitations in using structurally rigid or semirigid analogues to deduce stereostructure-activity relationships. Examples are given how this concept has been applied in the field of muscarinic agents, morphinomimetics and tryptamines.

In the light of the experience gained studying various sets of muscarinic ligands related to a rigid model, flexible structures such as alkyltrimethylammonium salts, ethers and esters of choline have been prepared and their affinities (pD2) have been studied. The quantitative structure-activity relationships (QSAR) show that the pD2 value is strongly dependent on hydrophobic and steric parameters of the ligand substituent. Moreover, two indicator variables are considered to take ito account extra-activities connected with ligand special structural features. The overall QSAR confirm that the electrostatic attraction, the hydrophobic bonding and the polar interaction holding the ligand on the receptor are individually weak; however, these three forces collectively permit a more complete utilization of the receptor binding site.

Oxotremorine, N-(4-pyrrolidino-2-butynyl)-2-pyrrolidone ([1]), is a muscarinic agent equal in potency to acetylcholine (3, 7). Its extraordinary potency is surprising in view of its structural dissimilarity to other muscarinic agents. Whereas most powerful muscarinic agents possess a quaternary trimethyl ammonium group, oxotremorine is a tertiary amine with no N-methyl groups at all. Moreover, it contains an acetylenic bond at the position in the molecule where strong muscarinic agents have an oxygen atom. The structural requirements for muscarinic activity are rather specific and even slight changes in the structure lead to loss of the muscarinic activity or to a change of the type of activity from agonistic to antagonistic (4, 14). The only amino congeners which show agonistic activity of the same order of magnitude as oxotremorine are the dimethylamino ([2]) and the azetidino ([3]) analogs. Compound [3] is in fact the most potent tertiary muscarinic agent known to date (see structures on next page).

Preparation of 6-endo and 6-exo-acetoxy-2-methylisoquinuclidine methiodides are described. Muscarinic assay data are reported. Neither of the compounds showed activity when compared to acetylcholine and 3-acetoxyquinuclidine methiodide.