Synthesis and evaluation of conformationally restricted pyridino N‐alkylated nicotine analogs as nicotinic acetylcholine receptor antagonists

Abstract

Previous work has shown that quaternization of the pyridine-N atom of S-(-)-nicotine (NIC) affords compounds such as N-n-octylnicotinium iodide (NONI) and N-n-decylnicotinium iodide (NDNI) that act as competitive nicotinic acetylcholine receptor (nAChR) antagonists at α3β2* and α4β2* subtypes, respectively. To ascertain the rotameric preference about the C3-C2′ bond of NONI and NDNI for interaction with several nAChR subtypes, two classes of bridged analogs representing extreme rotameric conformations (syn and anti) of NONI and NDNI were synthesized. interaction with α4β2* and α7* nAChR subtypes. Interestingly, the C 10 Nalkyl chain analogs, ACD and BCD, had negligible affinity for the α4β2* subtype compared to the high affinity exhibited by NDNI, suggesting that the α4β2* subtype does not recognize the unique stereochemistry of these conformationally restricted analogs. Thus, conformational restriction of N-nalkylnicotinium iodides eliminated inhibitory activity at α4β2* nAChRs, but more importantly afforded high affinity and selectivity for α3β2* nAChRs. Conformational restriction of N-n-alkyl analogs of NIC appears to be a viable approach for the development of α3β2*-selective nAChR antagonists. Drug Dev.

Expeditious synthesis of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo-[3,2h]isoquinoline/[2,3-f]quinoline via azomethine ylide-alkene [3+2] cycloaddition

“…Accordingly, when the mixture of 18 and sarcosine in DMF was heated at 110 °C for 4 h, the cycloadduct 1 was obtained in excellent yield (86 %). The 1 H and 13 C NMR spectrum of 1 were identical to that of an authentic sample prepared in this group previously following the route depicted in scheme 2 11 or the route of Glassco et al, 3, 13 who had established the cis -geometry of 1 through X-ray analysis. Only the cis -isomer was detected as the product of the intramolecular ylide-alkene [3+2] cycloaddition.…”

N-n-alkylnicotinium analogs, a novel class of antagonists at α4β2* Nicotinic acetylcholine receptors: Inhibition of S(-)-nicotine-evoked 86Rb+Efflux from rat thalamic synaptosomes

“…The remaining chemicals contained in the superfusion buffer were obtained from Fisher Scientifi c (Pittsburgh, PA). N-Methylnicotinium iodide (NMNI), N-n -propylnicotinium iodide (NPNI), N-n-butylnicotinium iodide (NnBNI), and NONI were prepared as described by Crooks et al 19 N -Ethylnicotinium iodide (NENI), N-n-hexylnicotinium iodide (NHxNI), N-n-heptylnicotinium iodide (NHpNI), N-n-nonylnicotinium iodide (NNNI), NDNI, and N-n-dodecylnicotinium iodide (NDDNI) were prepared from NIC and the appropriate n -alkyl iodide using the general procedure described by Xu et al 24 All synthesized compounds were fully characterized by elemental analysis and determined to be free from NIC using spectroscopic ( 1 H-and 13 C-nuclear magnetic resonance, and fast atom bombardment mass spectroscopy), thin layer chromatographic (silica gel), and combustion analysis procedures. Structures of the N-nalkylnicotinium analogs are provided in Figure 1 .…”

(Z)-2-(3-Hydroxy-4-methoxybenzylidene)-1-azabicyclo[2.2.2]octan-3-one

“…The nicotinic modulation of [ 3 H]dopamine release from striatal preparations has been exploited as a model system for examining native nicotine acetylcholine receptor (nAChR) responses (Soliakov & Wonnacott, 1996;Grady et al, 1997) and evaluating novel ligands (Holladay et al, 1997;Bencherif et al, 1998;Xu et al, 2002). 1-Azabicyclo[2.2.2]octane is a very important biological moiety, and its analogues are agonists at the 7 nAChR subtype, with selective af®nity for the 7 versus 4 2 nAChR subtype (Mullen et al, 2000).…”