John Saunders

A novel series of non‐quaternary oxadiazoles acting as full agonists at muscarinic receptors

1 A novel series of non‐quaternary oxadiazole‐based muscarinic agonists demonstrated high affinity for muscarinic receptors. 2 These agonists possessed high efficacy in the nanomolar range at muscarinic receptors in the superior cervical ganglion, atrium and ileum but did not show selectivity across the tissue preparations. 3 Two amino oxadiazoles, one from a quinuclidine series (L‐660,863) and one from a 1‐azanorbornane series (L‐670,207) possessed a high ratio of potency for displacing the binding of [3H]‐N‐methylscopolamine ([3H]‐NMS) to potency for displacing the agonist [3H]‐oxotremorine‐M ([3H]‐oxo‐M) (NMS/oxo‐M ratio) predictive of high efficacy in the cortex. 4 The two azanorbornane derivatives L‐670,548 and L‐670,207 stimulated the turnover of phosphatidylinositol in the cortex with a potency higher than that obtained with any other known muscarinic agonist (ED50 0.26 and 0.18 μm respectively). 5 The maximum response obtained with L‐670,207 was greater than that observed for carbachol but was comparable to that of the natural ligand acetylcholine. 6 These oxadiazole muscarinic agonists are among the most potent and efficacious non‐quaternary muscarinic agonists ever described.

Chapter 4. Central Muscarinic Ligands and Receptors

Publisher Summary This chapter discusses the structure and function of individual muscarinic receptors (MR) and also discusses the medicinal chemistry and biology of new ligands. Molecular biological techniques have furnished cloned porcine MR (mAChR) that correspond to the pharmacologically defined M 1 , M 2 (Mz α ,), and M 3 (M 3β ) receptors, respectively. For the beta receptor, the anionic site that interacts with the cationic head group of the ligand is an aspartic acid (ASP) residue buried within the membrane spanning domains of the protein. Chemical studies have supported the functional role of ASP residues on the MR. The interest in the possible application of cholinergic agonists in the treatment of cognitive disorders, such as Alzheimers disease, has stimulated substantial activity in the chemistry and properties of muscarinic agonists. The amino-oxadiazole proved to be the most potent and most efficacious nonquaternary muscarinic agonist known being 200-fold more potent than arecoline. A number of selective antagonists are now available that clearly differentiate between the different subtypes found in high density in neuronal tissues, peripheral effector organs, such as the heart, smooth muscle, and glands. Detailed binding and pharmacological studies have established methoctramine to be the most potent, selective antagonist of the cardiac M 2 muscarinic receptors. Although much remains to be done to unravel the functional roles of the central MR subtypes, it is likely that a combination of molecular biology and the use of subtype selective ligands can help to achieve this objective. Importantly, as far as the cholinergic hypothesis of Alzheimers disease is concerned, the M 1 receptor may be joined by another subtype, and this may redirect pharmaceutical research for the future.

L-687,306: a functionally selective and potent muscarinic M1 receptor agonist

The oxadiazole L-687,306 is a high affinity muscarinic agonist with a N-methylscopolamine/oxotremorine-M binding profile predictive of a partial agonist. L-687,306 showed marked selectivity in functional pharmacological assays. L-687,306 was a partial agonist at muscarinic M1 receptors in the rat ganglion but a high affinity competitive antagonist at guinea-pig cardiac M2 and ileal M3 muscarinic receptors. This compound gives an opportunity to study receptor reserve involved in muscarinic receptors in vitro and in vivo.

Synthesis of azabicyclic pyrazine derivatives as muscarinic agonists and the preparation of a chloropyrazine analogue with functional selectivity at sub-types of the muscarinic receptor

The synthesis of quinuclidine and azanorbornyl pyrazine derivatives has yielded highly potent and efficacious muscarinic agonists; chloro-substitution in the pyrazine ring of the quinuclidine analogue resulted in the formation of a derivative with both enantiomers displaying partial agonist character but, more importantly, functional selectivity at the M1, M2 and M3 sub-types of the muscarinic receptor.

The synthesis of 5- and 6-substituted quinuclidine-3-carboxylic esters: intermediates for novel muscarinic ligands

Quinuclidine-3-carboxylic esters bearing 5-hydroxy, 5-methyl and 6-methyl substituents are of interest as precursors to novel muscarinic ligands. All diastereoisomers of these disubstituted quinuclidines have been prepared, in each case using an appropriately substituted quinuclidin-3-one as the key intermediate. The keto ester 5a was obtained stereoselectively, either by intramolecular alkylation of a bromoacetylpiperidine, or by Dieckmann cyclisation of the differentially protected piperidine 18. 5-Methylquinuclidin-3-one was formed as a single isomer 24b by Dieckmann cyclisation. Piperidine-2,4-diester 33, in contrast, yielded a mixture of 2,5-disubstituted quinuclidine isomers 34 on cyclisation. Elaboration of the quinuclidinones gave the required esters, in several cases with high stereoselectivity. The stereochemical outcome of the Dieckmann cyclisation has been rationalised on the basis of molecular mechanics calculations.

Assignment of 13C-signals from the meso-carbons by syntheses of 13C-protoporphyrin-IX dimethyl esters

[β-13C]-, [γ-13C]-, and [δ-13C]-Protoporphyrin-IX dimethyl esters have been synthesised by unambiguous routes from [13C]formaldehyde to allow assignment of the four n.m.r. 13C-signals from the meso-carbons; the dimethyl ester of diacetyldeuteroporphyrin-IX has been similarly studied.