Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors, Part 1. N-(Phenylpropyl)-1-arylethylamines

Abstract

A series of 15 analogues of fendiline, and 34 derivatives of N-(3-phenylpropyl)-1-arylethylamine have been prepared for evaluation as positive allosteric modulators of GABAB receptors. The most active (EC50, 10 nM) was N-(3,3-diphenylpropyl)-1-(3-chloro-4-methoxyphenyl)ethylamine 6g.

THE CGP7930 ANALOGUE 2,6‐DI‐TERT‐BUTYL‐4‐(3‐HYDROXY‐2‐SPIROPENTYLPROPYL)‐PHENOL (BSPP) POTENTIATES BACLOFEN ACTION AT GABAB AUTORECEPTORS

“…data, 2006). BSPP, which has a spirocyclopentyl conformation, is structurally related to CGP7930 and was moderately active in potentiating baclofen‐induced hyperpolarizing responses at GABA B post‐synaptic receptors in rat neocortical slices 3 . However, neither BSPP nor CGP7930 has been examined for their pharmacological actions on GABA B presynaptic receptors.…”

“…The following drugs were used in the present study: 2,3‐[ 3 H]‐[N]‐GABA, specific activity 1.06 TBq/mmol, and L‐[3,4‐ 3 H]‐glutamic acid, specific activity 1.89 TBq/mmol (New England Nuclear, Boston, MA, USA); AOAA and semicarbazide (Sigma, St Louis, Mo, USA); NO‐711 (Research Biochemicals, Natick, MA, USA); racemic (±) baclofen (Tocris Cookson, Bristol, UK). Sch 50911 was a gift from Dr D Blythin (Schering Plough, Kenilworth, NJ, USA); BSPP was synthesised in‐house as described previously 3 …”

“…Many allosteric modulators have been described for GABA B receptors, including 2,6‐di‐ tert ‐butyl‐4‐(3‐hydroxy‐2,2‐dimethyl‐propyl)‐phenol (CGP7930), a structurally close analogue of the general anaesthetic agent propofol 2 . In a recent paper, a novel compound structurally related to CGP7930, namely 2,6‐di‐ tert ‐butyl‐4‐(3‐hydroxy‐2‐spiropentylpropyl)‐phenol (BSPP), was moderately active in potentiating baclofen‐induced hyperpolarizing responses in rat neocortical slices 3 . The latter action was mediated via post‐synaptic receptors, 3 but the action of BSPP at presynaptic GABA B auto‐ and heteroreceptors has not been examined previously.…”

“…In a recent paper, a novel compound structurally related to CGP7930, namely 2,6‐di‐ tert ‐butyl‐4‐(3‐hydroxy‐2‐spiropentylpropyl)‐phenol (BSPP), was moderately active in potentiating baclofen‐induced hyperpolarizing responses in rat neocortical slices 3 . The latter action was mediated via post‐synaptic receptors, 3 but the action of BSPP at presynaptic GABA B auto‐ and heteroreceptors has not been examined previously.…”

Immobilized Whole-Cell Transaminase Biocatalysts for Continuous-Flow Kinetic Resolution of Amines

“…To demonstrate the synthetic applicability of the selected novel immobilized whole-cell (S)-and (R)-selective TA biocatalysts, the KR of 1d was performed on a preparative scale in continuous-flow mode (Figure 2). The pure enantiomers of the drug-like compound 1d are potential building blocks for several reported drug candidates: Akincioglu [42] published a study of novel sulfamoyl carbamates and sulfamides as potential carbonic anhydrase and acetylcholine esterase inhibitors, while Kerr [43] studied the employment of N-(phenylpropyl)-1-arylethylamines as allosteric modulators of GABA B receptors with good results. These studies indicate the importance of efficient methods for production of the enantiomers amines like 1d.…”