Synthesis and Biological Evaluation of Meperidine Analogues at Monoamine Transporters

Abstract

A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at mu-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (K(i) = 0.0072 muM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and mu-opioid receptors (mu/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K(i) = 0.125 muM) and was the most selective ligand for the DAT over mu-opioid receptors (mu/DAT = 16.3) but remained slightly more selective for the SERT over the DAT(DAT/SERT = 6.68). Three compounds, the 3,4-dichlorophenyl derivative 7e and the 2-naphthyl analogues 6f and 7f, were identified that were more potent at the DAT than meperidine and that exhibited well-defined biphasic dopamine uptake inhibition similar to meperidine. However, none of the analogues tested produced locomotor effects or substituted for cocaine in drug discrimination studies, suggesting that the mu-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.

Further structure–activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters

“…Binding affinities for the dopamine, serotonin and norepinephrine transporters were determined by the ability of the drug to displace the radiolabeled ligands [ 3 H]WIN 35,428, [ 3 H]citalopram, and [ 3 H]nisoxetine, respectively, from the monoamine transporters obtained from rat brain tissue using previously reported assays. 40, 43,44 The binding affinities of all compounds listed in Table 1 were initially determined for the DAT. The compounds that exhibited DAT binding affinities with K i values < 100 nM were evaluated at the serotonin and norepinephrine transporters to determine transporter selectivity.…”

Synthesis and structure–activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands

“…Based upon previous structure-activity studies of meperidine analogues, 21 we focused on four 4-aryl (Ar 1 ) piperidine scaffolds (Ar 1 = 3,4-dichlorophenyl, 4-Ph-Ph, 4-I-Ph, 2-naphthyl). Previous studies had shown these aryl groups to contribute to the high potency and selectivity at SERT observed for the meperidine ethyl ester derivatives 2a-d (Table 1) as well as a variety of piperidine and tropane derivatives.…”

“…The benzyl ester derivatives were prepared from the corresponding nitriles 5 (Scheme 1) that were readily available using synthetic methods previously reported from our laboratory. 21 Hydrolysis of the nitrile moiety of 5 was achieved in a methanolic solution of sodium hydroxide (25% wt) at reflux, followed by an acidic work-up (2N HCl) to afford the carboxylic acids 6 as the hydrochloride salts in >90% yield. Without purification, the carboxylic acids 6 were converted into the acid chlorides 7 with thionyl chloride and then treated with the appropriately substituted benzyl alcohol under phase-transfer conditions.…”

“…Although meperidine exhibits sub-micromolar affinity for u-opioid receptors ( K i = 0.92 μM), previous structure-activity studies with substituted aryl analogues revealed that the 3,4-dichlorophenyl, 4-iodophenyl and 2-naphthyl meperidines exhibited reduced affinity at μ-opioid receptors. 21 Therefore evaluation of μ-opioid receptor affinity was deemed unnecessary at this time.…”

“…20-23 Previously, we have reported on a series of derivatives of meperidine ( 1 ) that exhibited modest potency and selectivity for the SERT (Figure 2). 21,22 However, unlike the prototypical SSRIs fluoxetine and paroxetine, the meperidine analogues 2 lack a secondary amine and two aromatic moieties common to the SERT pharmacophore. 24,25 In light of these deficiencies it was of interest to examine this class of meperidine-based SERT ligands to determine if SERT potency could be improved and the monoamine transporter selectivity influenced by the addition of a second strategically placed aryl ring system.…”