Orexin Receptor Antagonism: A New Principle in Neuroscience

Orexins are hypothalamic neuropeptides interacting with G-protein coupled receptors in the brain. They play a role in the regulation of sleep–wake cycles in mammals, as suggested by the deficits in orexinergic function that are associated with rodent, canine and human narcolepsy. Selective or dual orexin1-receptor and/or orexin2-receptor antagonists or agonists that cross the blood-brain-barrier (BBB) may be of therapeutic interest for disorders of disturbed arousal and alertness. This article summarizes recent research to identify and characterize orexin receptor antagonists and their therapeutic potential for normalizing sleep in insomnia patients

Lewis acid catalyzed reactions of thioketones with 1,2-epoxycyclohexane and 1,2-epoxycyclopentane

Non-enolizable thioketones and 1,2-epoxycycloalkanes undergo a Lewis acid catalyzed addition reaction to give 1,3-oxathiolanes. Appropriate reaction conditions are CH2Cl2 as the solvent, BF 3.Et2O as the Lewis acid, and a temperature between -78° and r.t. Under the reaction conditions, the 1,3-oxathiolanes are only moderately stable. They decompose to yield the corresponding epithiocycloalkane and ketone. In general, 1,3- dithiolanes are isolated as minor products or, after prolonged reaction, as the main product. These secondary products are formed via the Lewis acid catalyzed reaction of the intermediate epithiocycloalkane and a second molecule of the thioketone. In the reaction of thiobenzophenone and 1,2-epoxycyclohexane, trans-8,8-diphenyl-7,9-dioxabicyclo[4.3.0]nonane is formed in small amounts as an additional side product (Scheme 12). In all cases, the newly formed heterocycle and the carbocycle are trans-fused. This result is consistent with a nucleophilic ring-opening of the complexed oxirane by the thioketone via inversion of the configuration and subsequent formation of the O(1)-C(2) bond of the 1,3-oxathiolane (Scheme 13). The surprising formation of the fused 1,4-oxathiepan derivative 23 (Scheme 9) is in accordance with an ionic reaction mechanism (cf. Scheme 15)

Tetrahydroisoquinolines as Orexin Receptor Antagonists: Strategies for Lead Optimization by Solution-Phase Chemistry

Different techniques can be applied for the automated production of small and large compound collections. Large libraries that are often generated and tested during the lead-finding stage of a project are typically produced by solid-phase chemistry. Libraries that are significantly smaller in size are often synthesized in solution. Chemistry in solution is rather versatile, offers numerous advantages and is therefore often the method of choice for generating small libraries during a lead optimization process. Fast and reliable purification procedures are required to yield compounds of high quality that can be immediately used in biological as well as pharmacological assays. Solution-phase chemistry combined with automated purification was applied to optimize initial lead inhibitors for the two human orexin receptors OX1 and OX2. Starting from a submicro-molar OX1 selective lead compound, low nanomolar analogues with improved physico-chemical properties were synthesized that antagonize either one or both orexin receptors