Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors, Part 2. 3-(2,6-Bis-tert-butyl-4-hydroxyphenyl)propanols

Abstract

A series of 13 2,2-disubstituted 3-(3,5-di-t-butyl-4-hydroxyphenyl)propan-1-ol derivatives have been prepared for evaluation as allosteric modulators of GABAB receptors. The activity (EC50, 4–7 μM) was greatest for the cyclohexyl and cyclopentyl analogues.

Synthesis and biological activity of allosteric modulators of GABA B receptors part 3. 3-(2,6-bis-iso-propyl-4-hydroxyphenyl)propanols

“…9 The resulting carbonyl compounds (7a-d) were either reduced with sodium borohydride to the alcohols (8a, 8b, 9a, 9c), or reacted with alkyllithium reagents to give a mixture of diastereoisomers of alcohol (9b) (Scheme 1).…”

“…Accordingly, we have recently synthesized a series of compounds modifying the structure 2, all of which acted as positive modulators at GABA B receptors. 9 The most active was the cyclohexyl analogue (5), which was 2 to 3 times as active as the lead compound (2). Our working hypothesis for the lead compound (2) is that it acts through the 3-hydroxyphenylpropyl moiety, with the hydroxyphenyl group corresponding to the carboxyl group of GHB, in addition to providing hydrophobic properties that would facilitate transport across cell membranes.…”

“…Following a random mass screening, Urwyler et al 1 recently reported that 2,6-di-tert-butyl-4-(3-hydroxyphenyl)-2,2-dimethylpropionaldehyde, CGP 13501, (1) acted as a positive allosteric modulator for GABA B receptors, 2,3 and its reduction product, the corresponding alcohol CGP 7930 (2) was found to be even more potent. Because of our interest in such modulators, 2,4,5 we speculated that the latter could be regarded as a hybrid of propofol (3) and hydroxybutyric acid (GHB, 4).…”

“…Because of our interest in such modulators, 2,4,5 we speculated that the latter could be regarded as a hybrid of propofol (3) and hydroxybutyric acid (GHB, 4). Propofol 6,7 is a shortacting hypnotic agent (GABA A modulator), effective for induction and maintenance of anaesthesia when administered intravenously either as repeated bolus injections or by continuous infusion.…”

“…Our working hypothesis for the lead compound (2) is that it acts through the 3-hydroxyphenylpropyl moiety, with the hydroxyphenyl group corresponding to the carboxyl group of GHB, in addition to providing hydrophobic properties that would facilitate transport across cell membranes. Since our previous work 9 was concerned mainly with an examination of the effect of changing the hydrophobicity and steric bulk near the hydroxyl end of the molecule, we now report the preparation of some variants at the phenolic portion of the molecule; at this stage little is known of the pharmacokinetics of these compounds, and their therapeutic potential is uncertain. The basic synthetic approach continues to be basically that of Urweyler et al…”