Acyclic analogs of 2-(4-phenylpiperidino)cyclohexanol (vesamicol): conformationally mobile inhibitors of vesicular acetylcholine transport

Abstract

Several 1,3-disubstituted propan-2-ols and one alpha,beta-disubstituted ethanol (11i) were synthesized and evaluated as potential acyclic mimics of the vesicular acetylcholine transport inhibitor 2-(4-phenylpiperidinyl)cyclohexanol (1, vesamicol, AH5183). Analogues containing the 4-phenylpiperidyl fragment (11a, 11b) were more potent than those containing the 4-phenylpiperazyl moiety (11e, 11f). Substitution at the second terminal carbon of the propyl (or ethyl) fragment with simple lipophilic aryl substituents yielded potent inhibitors of vesicular acetylcholine storage, including (-)-11a and d-11i, which are equipotent with vesamicol. However, the activity of analogues containing bicyclic aryl groups was susceptible to aryl substitution patterns (11g vs 11h), indicating a definite receptor site topography. In addition, the inhibitory activity of these acyclic analogues was enantioselective, exhibiting a preference, similar to the parent vesamicol, for the levorotatory isomer [(-)-11a vs (+)-11a]. Therefore, the simple lipophilic acyclic vicinal amino alcohols may successfully mimic the biological activity of vesamicol.

Practical Iron‐Catalyzed Allylations of Aryl Grignard Reagents

“…Reactions with reduced catalyst loading (0.2-1 mol%) showed excellent selectivities (entries 7, 8,17,20,21). A turnover number of 430 and a turnover frequency of 860 h À1 was observed with 0.2 mol% FeA C H T U N G T R E N N U N G (acac) 3 after 0.5 h (entry 8).…”

“…In the absence of catalyst, rapid double arylation of the carbonyl function was observed. Reactions of arylGrignard species with allyl bromide in refluxing THF have been reported, [21] while no conversion was observed after 2 h at 0 8C (Scheme 2).…”

Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate

“…The tris(3,5-dimethylphenylcarbamate) cellulose coated silica column (Chiralcel OD) was selected based on the structure of the racemic compounds; (±)- 5–7 possess a hydroxyl group on the chiral center, the Chiralcel OD column is known to be highly efficient in resolving compounds with similar hydroxyl chirality. 29 A mixture of hexane and 2-propanol was used for the mobile phase. Under these separation conditions, the enantiomers of (±)- 5–7 were successfully resolved with an enantiomeric excess > 95% as determined by chiral analytical HPLC (Chiralcel OD column, 250 × 4.6 mm).…”

“…Similar binding trends have been observed for other VAChT compounds with similar structures. 15, 29 Enantiomers (+)- 6 , (−)- 6 , (+)- 7 , (−)- 7 displayed good potency for VAChT with K i value less than 5 nM; at 4.35, 0.37, 2.31, and 0.31 nM, respectively; (−)- 7 was the most potent compound with K i value of 0.31 nM for VAChT. In addition, (−)- 7 displayed >5000-fold selectivity for VAChT over σ 1 receptor although enantiomeric (+)- 5 , (−)- 5 , (+)- 6 , (−)- 6 had moderate to good selectivity over σ 1 receptor (6–430-folds).…”

Sodium dithionite initiated addition of 1-bromo-1-chloro-2,2,2-trifluoroethane to allylaromatics

“…Allylbenzenes 1a-1l, allylnaphthalene 1n and allylpyridines 1o-1p were prepared by allylation of the adequate magnesium aryl bromides with allylbromide [12][13][14][15].…”