Lobeline esters as novel ligands for neuronal nicotinic acetylcholine receptors and neurotransmitter transporters.

Abstract Vesicular monoamine transporter-2 (VMAT2) is a viable target for development of pharmacotherapies for psychostimulant abuse. Lobeline ( 1 ) is a potent antagonist at α4β2∗ nicotinic acetylcholine receptors, has moderate affinity ( K i  = 5.46 μM) for VMAT2, and is being investigated currently as a clinical candidate for treatment of psychostimulant abuse. A series of carboxylic acid and sulfonic acid ester analogs 2 – 20 of lobeline were synthesized and evaluated for interaction with α4β2∗ and α7∗ neuronal nicotinic acetylcholine receptors (nAChRs), the dopamine transporter (DAT), serotonin transporter (SERT) and VMAT2. Both carboxylic acid and sulfonic acid esters had low affinity at α7∗ nAChRs. Similar to lobeline ( K i  = 4 nM), sulfonic acid esters had high affinity at α4β2∗ ( K i  = 5–17 nM). Aromatic carboxylic acid ester analogs of lobeline ( 2 – 4 ) were 100–1000-fold less potent than lobeline at α4β2∗ nAChRs, whereas aliphatic carboxylic acid ester analogs were 10–100-fold less potent than lobeline at α4β2∗. Two representative lobeline esters, the 10- O -benzoate ( 2 ) and the 10- O -benzenesulfonate ( 10 ) were evaluated in the 36 Rb + efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC 50 values of 0.85 μM and 1.60 μM, respectively. Both carboxylic and sulfonic acid esters exhibited a range of potencies (equipotent to 13–45-fold greater potency compared to lobeline) for inhibiting DAT and SERT, respectively, and like lobeline, had moderate affinity ( K i  = 1.98–10.8 μM) for VMAT2. One of the more interesting analogs, p -methoxybenzoic acid ester 4 , had low affinity at α4β2∗ nAChRs ( K i  = 19.3 μM) and was equipotent with lobeline, at VMAT2 ( K i  = 2.98 μM), exhibiting a 6.5-fold selectivity for VMAT2 over α4β2 nAChRs. Thus, esterification of the lobeline molecule may be a useful structural modification for the development of lobeline analogs with improved selectivity at VMAT2.