Pharmacophore, muscarinic

Superpositioning these three potent muscarinic agents, in their preferred conformations resulted in the observation of a common pattern of similarly charged structural features. The pattern, Figure 4, was proposed as the muscarinic pharmacophore (8). This pattern, predicted from theoretical considerations, bears a striking similarity to the muscarinic pharmacophore proposed by Beckett based on extensive structure—activity studies... 

Calculations on oxotremorine (15), presumed to be a CNS muscarinic agent, revealed that this molecule, in its predicted conformation (Figure 5) mimicks this predicted muscarinic pharmacophore. The assumption is made that the electronic character of the triple bond is the receptor equivalent of the ether oxygen atom in acetylcholine as proposed by Bebbington (16). These calculations support his proposal and reveal how oxotremorine may meet the structural requirements of a muscarinic agent. 

Holtje, H.D. (1974) Molecular orbital calculations for the structure of the muscarine-pharmacophore. Archiv der Pharmazie (Weinheim), 307, 969-972. 

DP Mamott, IG Dougall, P Meghani, Y-J Liu, DR Flower. Lead generation using pharmacophore mapping and three-dimensional database searching Application to muscarinic M3 receptor antagonists. J Med Chem 42 3210-3216, 1999. 

Biocatalysis has emerged as an important tool for the enantioselective synthesis of chiral pharmaceutical intermediates and several review articles have been published in recent years [133-137]. For example, quinuclidinol is a common pharmacophore of neuromodulators acting on muscarinic receptors (Figure 6.50). (JJ)-Quinudidin-3-ol was prepared via Aspergillus melleus protease-mediated enantioselective hydrolysis of the racemic butyrate [54,138]. Calcium hydroxide served as a scavenger of butyric acid to prevent enzyme inhibition and the unwanted (R) enantiomer was racemized over Raney Co under hydrogen for recycling. 

Muscarinic M3 Receptor. A pharmacophore model was derived from known M3 receptor antagonists, using the program DISCO, and 3D searching was performed by Unity 3D in the Astra Charnwood in-house compound repository and the databases of several commercial suppliers. The 172 compounds that fitted the pharmacophore were screened for their M3-antagonistic potency. Several compounds with micromolar and even submicromolar activities resulted, for example, compound 13 (A50 M3 antagonism 0.2pM pA2 = 6.67 Fig. 16.2) [85],... 

Depending on which face it puts forward, a single dmg molecule may interact with more than one receptor and thus may have more than one pharmacophoric pattern. For example, one bioactive face of acetylcholine permits interaction with a muscarinic receptor, while another bioactive face of acetylcholine permits interaction with a nicotinic receptor (section 4.2). Similarly, the excitatory neurotransmitter glutamate may bind to a range of different receptors, such as the NMDA and AMPA receptors (section 4.7), depending upon the pharmacophoric pattern displayed by the glutamate molecule toward the receptor with which it is interacting. 

Muscarinic M3 AstraZeneca in-house (N.R.) DISCO/UNITY Ligand-based pharmacophore 172 1.7 3 (213 nM) [50]... 

Muscarinic Agonists—Towards a Common Pharmacophore Model for Enantiomers with Very Different Biological Potency. ... 

Holzgrabe, U. and Hopfinger, A.J. (1996). Conformational Analysis, Molecular Shape Comparison, and Pharmacophore Identification of Different Allosteric Modulators of Muscarinic Receptors. J.Chem.lnfComput.ScL, 36,1018-1024. 

Holzgrabe, U., Hopfinger, A.J., 1996. Conformational analysis, molecular shape comparison and pharmacophore identification of different allosteric modulators of muscarinic receptors. J. Chem. Inf. Comp. Sci. 36, 1018-1024. 

Ward, J.S., Merritt, L., Klimkowski, VJ., Lamb, M.L., Mitch, C.H., et al. (1992) Novel functional M) selective muscarinic agonists. 2. Synthesis and structure-activity relationships of 3-pyrazinyl-l,2,5,6-tetrahydro-l-methylpyridines. Construction of a molecular model for the M pharmacophore. /. Med. Chem. 35 4011-4019. 

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