Novel 5-HT3 antagonists: indol-3-ylspiro(azabicycloalkane-3,5'(4'H)oxazoles)

• Published in: Journal of medicinal chemistry Vol. 35; no. 6; pp. 1019 - 1031
• Main Authors: Swain, C. J, Baker, R, Kneen, C, Herbert, R, Moseley, J, Saunders, J, Seward, E. M, Stevenson, G. I, Beer, M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-03-1992
• Subjects: Animals; Binding Sites - drug effects; Brain - drug effects; Brain - metabolism; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - metabolism; Bridged Bicyclo Compounds - pharmacology; Chemistry; Condensed matter: structure, mechanical and thermal properties; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Indoles - chemical synthesis; Indoles - metabolism; Indoles - pharmacology; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Organic chemistry; Organic compounds; Oxazoles - chemical synthesis; Oxazoles - metabolism; Oxazoles - pharmacology; Physics; Preparations and properties; Rats; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - metabolism; Serotonin Antagonists - pharmacology; Stereoisomerism; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Structure-Activity Relationship; X-Ray Diffraction; Five membered ring; Molecular structure; Nitrogen heterocycle; Serotonin antagonist; Model study; Experimental study; X ray diffraction; Spiran; Structure activity relation; Spirocyclization; Steric effect; Bicyclic compound; Oxygen nitrogen heterocycle; Biological receptor; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00084a007

The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.