Piperidine Derivatives. Part 1. Lobelan and Related Compounds

Lee, John; Freudenberg, Werner

doi:10.1021/jo01188a007

Cited by 14 publications

(19 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acyclic compound 26 33 and 27 34 (Figure 2) were prepared as previously reported. The nor-1-naphthyl and nor-2-naphthyl compounds 28a and 29a were prepared according to the procedure utilized to prepare norlobelane (20), 32 except that 1-or 2-naphthaldehyde was used instead of benzaldehyde (Scheme 4). NMethylation was then carried out using NaCNBH 3 /(CH 2 O) n to afford the corresponding Nmethyl compounds, 28b (1-NAP-lobelane) and 29b (2-NAP-lobelane).…”

Section: Chemistrymentioning

confidence: 99%

“…19.2, 28.7, 29.0, 32.0, 33.1, 40.5, 58.6, 61.9, 125.9, 126.3, 127.5, 128.3, 128.5, 128.6, 131.3, 131.4, 137.1 N-Methyl-2,6-cis-diphenethyl-1,2,3,6-tetrahydro-pyridine (17)-Compound 15 (colorless crystals recrystallized from benzene, mp 167-168 °C) was synthesized from the condensation reaction of 2,6-lutidine with benzaldehyde utilizing the reported procedure. 32 The double bonds of the 2,6-side chains of compound 15 were then reduced by Pd-C catalytic hydrogenation, and the resulting product was treated with methyl ptoluenesulfonate following the reported procedure, 32 to afford the N-methylated compound 16 (yellow crystals recrystallized from methanol, mp 238-239 °C). NaBH 4 (160 mg, 4.22 mmol) was added to a suspension of compound 16(2.00 g, 4.22 mmol) in absolute ethanol (100 mL) at 0 °C.…”

Section: Experimental Section Chemistrymentioning

confidence: 99%

See 1 more Smart Citation

Defunctionalized Lobeline Analogues: Structure−Activity of Novel Ligands for the Vesicular Monoamine Transporter

et al. 2005

View full text Add to dashboard Cite

Abstract(−)-Lobeline (2R,6S,10S; 1a), an antagonist at nicotinic acetylcholine receptors (nAChRs), inhibits the neurochemical and behavioral effects of methamphetamine and inhibits dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. VMAT2 is a target for the development of treatments for methamphetamine abuse. Structural modification of lobeline affords the defunctionalized analogues meso-transdiene (MTD) and lobelane, which have high potency and selectivity for VMAT2. To establish the structure-activity relationships within this novel class of VMAT2 ligands, specific stereochemical forms of MTD, lobelane, and other structurally related analogues have been synthesized. Generally, all of these analogues had lower affinities at α4β2* and α7* nAChRs compared to lobeline, thereby increasing selectivity for VMAT2. The following structural modifications resulted in only modest changes in affinity for VMAT2, affording analogues that were less potent than the lead compound, lobelane: (1) altering the stereochemistry at the C-2 and C-6 positions of the piperidino ring, (2) varying unsaturation in the piperidino C-2 and C-6 substituents, (3) introducing unsaturation into the piperidine ring, (4) ring-opening or eliminating the piperidine ring, and (5) removing the piperidino N-methyl group. Furthermore, incorporating a quaternary ammonium group into defunctionalized lobeline molecules in the cis-series resulted in significant loss of affinity for VMAT2, whereas only a modest change in affinity was obtained in the transseries. The most potent (K i = 630 nM) and VMAT2-selective compound evaluated was the Nmethyl-2,6-cis-bis(naphthaleneethyl)piperidine analogue 28b (1-NAP-lobelane), in which the phenyl groups of lobelane were replaced with 1-naphthyl moieties. Thus, initial structure-activity relationship studies reveal that the most promising structural changes to the lobeline molecule that lead to enhancement of VMAT2 affinity and selectivity are defunctionalization, affording lobelane and MTD, and replacement of the phenyl rings of lobelane with other aromatic moieties that have a π-extended structure.

show abstract

Section: Chemistrymentioning

confidence: 99%

Section: Experimental Section Chemistrymentioning

confidence: 99%

Defunctionalized Lobeline Analogues: Structure−Activity of Novel Ligands for the Vesicular Monoamine Transporter

et al. 2005

View full text Add to dashboard Cite

show abstract

“…The synthesis of 14b and 15b was initiated from the condensation reaction of 2,4-lutidine with benzaldehyde. 28 The resulting highly conjugated product, 13b, was reduced to compound 14b under Adam s reduction conditions. 28 N-Methylation was then carried out utilizing NaCNBH 3 /para-formaldehyde to form compound 15b (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

“…28 2,4-Lutidine (1 equiv for synthesis of 14b), or 2,6-dimethylpyrazine (for synthesis of 14c), or 2-picoline (for synthesis of 17a), or 4-picoline (for synthesis of 17c), or 2,6-lutidine (for synthesis of nor-lobelane, 24a-34a, and 35), was mixed with the appropriate aryl aldehyde (1.05 equiv for picolines and 2.1 equiv for 2,6-dimethylpyrazine and lutidines) (for compound 35, 4-hydroxybenzaldehyde was used) and acetic anhydride. The mixture was refluxed under N 2 for 48-72 h and then cooled to room temperature.…”

Section: General Procedures For Synthesis Of Compounds 14a-c 17a-c Nmentioning

confidence: 99%