Development of a Two-Step Route to 3-PBC and βCCt, Two Agents Active against Alcohol Self-Administration in Rodent and Primate Models

Abstract

In order to gain access to 3-propoxy-β-carboline hydrochloride (3-PBC·HCl) (1·HCl), and β-carboline-3-carboxylate-t-butyl ester (βCCt) (2), potential clinical agents active against alcohol self-administration, a two-step route was developed. This process involves a palladium catalyzed Buchwald-Hartwig coupling and an intramolecular Heck reaction. This two-step route provides rapid access to multigram quantities of 3-PBC (1) and βCCt (2), as well as analogs for studies of alcohol self-administration. The overall yield of 3-PBC (1) was improved from 8 % to 50 % in this route.

Early life stress is a risk factor for excessive alcohol drinking and impulsivity in adults and is mediated via a CRF/GABAA mechanism

“…3-propoxy-9H-pyrido[3,4-b]indole hydrochloride, commonly known as 3-propoxy-β-carboline hydrochloride (3-PBC), acting at the GABAA1/2 receptor, was obtained from Dr. James Cook at the University of Wisconsin-Milwaukee [Milwaukee, WI] (Namjoshi et al, 2011). Antalarmin hydrochloride, a CRF antagonist, was obtained from R&D Systems Inc. [Minneapolis, MN].…”

Effects of the benzodiazepine GABAA α1-preferring ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), on alcohol seeking and self-administration in baboons

“…Isolation of the precise roles of the specific GABA receptor subtypes is currently being investigated using a series of β-carboline ligands that bind preferentially to the α1 receptor subtype (Yin et al 2010; Namjoshi et al 2011). One promising ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), displays 10-fold selectivity for the α1 subtype over the α2 and α3 receptors, as well as over 150-fold selectivity for the α1 subtype over the α5 subtype (Harvey et al 2002).…”

Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

“…With the previous history in mind 35 , the initial attempt was made with 5 mol% Pd(OAc) 2 , 7.5 mol% X-Phos and Cs 2 CO 3 (1.5 equiv) in toluene at 110 °C which gave only 18% of the diarylamine 16 with a large excess of unreacted starting material even after heating for 24 hours (Table 1, entry 1). However, the catalyst based on the combination of Pd 2 (dba) 3 , Xantphos and Pd(OAc) 2 , Xantphos with Cs 2 CO 3 in toluene and dioxane gave the desire product diarylamine 16 in up to 62% yield (Table 1, entries 2 – 3).…”

“…The process provided improved yields when compared to the earlier reported syntheses. 33, 35 This two-step protocol consists of the combination of a regioselective Buchwald-Hartwig amination and an intramolecular Heck-type cyclization. The first step, regioselective arylamination, was achieved by using a Pd-BINAP catalytic system in combination with a large excess of Cs 2 CO 3 , while the latter intramolecular Heck-type cyclization went smoothly with Pd(OAc) 2 in combination with the air-stable monodentate ligand ( t -Bu) 3 ·HBF 4 and K 2 CO 3 .…”

“…mp 120.5 – 121.5 °C (lit. 35 mp 119.3 – 120.5 °C) : 1 , 1 H NMR (300 MHz, CDCl 3 ) δ 8.66 (br, 1H), 8.42 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.45–7.38 (m, 1H), 7.35 (s, 1H), 7.21 (t, J = 7.4 Hz, 1H), 4.28 (t, J = 6.7 Hz, 2H), 1.94–1.78 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 157.9, 142.4, 133.8, 132.7, 128.9, 128.7, 122.0, 121.4, 119.5, 111.5, 99.1, 68.6, 22.7, 10.6; HRMS (ESI-TOF) ( m/z ): [M+H] + calcd for C 14 H 15 N 2 O: 227.1184, found: 227.1174. A hydrochloride salt of 1 was prepared by the reported method 31 to obtain 3-PBC·HCl ( 1·HCl ): yellow solid; mp 194.5 – 195.5 °C (lit 31 194.0 – 195.0 °C).…”