Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action

Abstract

We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT 2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT 2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyltrans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT 2C receptor agonists with selectivity over both 5-HT 2A and 5-HT 2B receptors in functional assays. The most promising compound is 37 with 120-and 14-fold selectivity over 5-HT 2A and 5-HT 2B , respectively (EC 50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.

Optimization of 2-Phenylcyclopropylmethylamines as Selective Serotonin 2C Receptor Agonists and Their Evaluation as Potential Antipsychotic Agents

“…The absolute configurations of the enantiomers were assigned from the measured optical rotations coupled with the stereochemical correlations reported previously by us. 21 …”

“…This particular scaffold was derived from an initial high throughput screening (HTS) screening campaign in which tranylcypromine was identified as a hit as described in an earlier publication. 21 Rational drug design principles coupled with the evolution of a body of structure–activity relationships (SARs) led to the identification of compounds possessing a 2-cyclopropylmethoxy group at position 2, as illustrated by compounds 8, 9 , and 10 (Figure 2). Compound 8 , which possesses a fluorine substitution at position 5 of the benzene ring, showed good potency on the 5-HT 2C receptor (EC 50 = 21 nM), with only moderate selectivity for 5-HT 2B (EC 50 = 289 nM).…”

Guide to enantioselective dirhodium(II)-catalyzed cyclopropanation with aryldiazoacetates

“…1,2 We have previously shown the rhodium-catalyzed cyclopropanation of donor/acceptor carbenoids to be effective for the enantioselective synthesis of cyclopropanes with one or more quaternary stereogenic centers. 3-6 As many cyclopropyl amines are known to have significant CNS activity, 7,8 we have initiated a program to use our cyclopropanation methodology to access novel diarylcyclopropylamines as potential the rapeutic agents (Scheme 1). For the methodology to be broadly useful in drug discovery, access to a range of diarylcyclopropyl derivatives with high levels of enantioenrichment is required.…”

Design, synthesis and biological evaluation of GPR55 agonists

“…A Wittig reaction, using methyltriphenylphosphonium iodide, was conducted to prepare 2-bromo-6-vinylnaphthalene 15 . 27 Hydroboration and oxidation of 15 gave the anti-Markovnikov alcohol 16 . 28 Protection of the alcohol was done using TBSCl in basic conditions 29 to generate bromide 18 .…”