Chemical Requirements for Inhibition of Gap Junction Communication by the Biologically Active Lipid Oleamide

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 9; pp. 4810 - 4815
• Main Authors: Boger, Dale L., Patterson, Jean E., Guan, Xiaojun, Cravati, Benjamin F., Lerner, Richard A., Gilula, Norton B.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 28.04.1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Agonists; Alkenes; Amides; Amidohydrolases - metabolism; Animals; Biochemistry; Cell Communication - drug effects; Cells, Cultured; Chemicals; Dyes; Fatty acids; Gap junctions; Gap Junctions - drug effects; Hydrogen bonds; Isomerism; Lipids; Neuroglia; Neuroglia - drug effects; Oleic Acids - chemistry; Oleic Acids - metabolism; Oleic Acids - pharmacology; Physical Sciences; Rats; Structure-Activity Relationship
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.9.4810

Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and has been shown to effect serotonergic systems and block gap junction communication in a structurally specific manner. Herein, the structural features of oleamide required for inhibition of the gap junction-mediated chemical and electrical transmission in rat glial cells are defined. The effective inhibitors fall into two classes of fatty acid primary amides of which oleamide and arachidonamide are the prototypical members. Of these two, oleamide constitutes the most effective, and its structural requirements for inhibition of the gap junction are well defined. It requires a chain length of 16-24 carbons of which 16-18 carbons appears optimal, a polarized terminal carbonyl group capable of accepting but not necessarily donating a hydrogen bond, a Δ9cis double bond, and a hydrophobic methyl terminus. Within these constraints, a range of modifications are possible, many of which may be expected to improve in vivo properties. A select set of agents has been identified that serves both as oleamide agonists and as inhibitors of fatty acid amide hydrolase, which is responsible for the rapid inactivation of oleamide.