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

Abstract

Vescular 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 (Ki=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 (Ki=4 nM), sulfonic acid esters had high affinity at α4β2* (Ki=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 36Rb+ efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC50 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 (Ki=1.98–10.8 μM) for VMAT2. One of the more interesting analogs, p-methoxybenzoic acid ester 4, had low affinity at α4β2* nAChRs (Ki=19.3 μM) and was equipotent with lobeline, at VMAT2 (Ki=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.

Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis

“…Competition binding studies with the α 7 -nicAchR selective ligand [ 3 H]-MLA were conducted in rat hippocampal membranes [16, 18]. In contrast to nicotine and lobe-line, lobinaline has similar affinity at α 4 β 2 - and α 7 -nicAchRs ( see Table 2 for comparison ) [80, 81]. Lobinaline produced a DDR value of 1.32, virtually identical to that produced by the CHCl 3 fraction, indicating lobinaline was the main metabolite responsible for the fraction’s nicAchR binding activity.…”

“…The alkaloid inhibited binding of the α 4 β 2 -nicAchR selective ligand [ 3 H]-cytisine (K i = 1.066 μM), and the α 7 -nicAchR selective ligand [ 3 H]-MLA (K i = 67.53 μM), in rat cortical and hippocampal membranes, respectively, and produced a DDR value of 1.32 [1, 16–18]. Compared to other plant metabolites, such as nicotine and lobeline, lobinaline is relatively non-selective with respect to α 4 β 2 - and α 7 -nicAchRs ( see Table 2 for comparison) [80, 81]. The plant metabolite anabasine is also non-selective at α 4 β 2 - and α 7 -nicAchRs (K i = 65 nM and 58 nM at α 4 β 2 - and α 7 -nicAchRs, respectively) [1].…”

“…In rat striatal membranes, binding of the highly selective DAT ligand [ 3 H]-GBR12935 was inhibited by lobinaline (K i = 2.543 μM), and the alkaloid dose-dependently attenuated DAT-mediated [ 3 H]-DA uptake (IC 50 = 11.95 μM) in rat striatal synaptosomes [53, 54]. Lobeline also inhibits the DAT, but is less potent (IC 50 = 28.2 – 80.0 μM) than lobinaline [23, 80]. In contrast, nicotine is inactive at the DAT in rat striatal synaptosomes [23].…”

Synthesis of Lobeline, Lobelane and their Analogues. A Review

“…A series of carboxylic acid esters ( 24 ) and sulfonic acid esters ( 25 ) of (−)-lobeline ( 1 ) has been reported by Hojahmat et al 21 These lobeline derivatives were synthesized by reacting 1 with various acyl chlorides and sulfonyl chlorides (Scheme 7). To minimize the epimerization of the products, the acylation and sulfonylation reactions were conducted in the absence of base.…”

HPLC‐ESI‐MS/MS of brain neurotransmitter modulator lobeline and related piperidine alkaloids in Lobelia inflata L

“…More recent studies suggest that lobeline may be a treatment for methamphetamine abuse and its associated neurotoxicity, which is currently in clinical trial. The underlying pharmacological mechanism thought to involve alteration of vesicular storage and release of DA through an interaction with VMAT2 . Therefore, structurally modified lobeline derivatives, meso‐transdiene and lobelane were prepared, which have high potency and selectivity for VMAT2 relative to nicotinic receptor binding …”