Quinuclidine Series Research Articles

Kinetic and Mechanistic Studies on Quinuclidinolysis of Y‐substituted‐Phenyl Picolinates: Effect of Amine Nature on Reactivity and Transition‐State Structure

Second‐order rate constants (k N) have been measured spectrophotometrically for reactions of Y‐substituted‐phenyl picolinates (7a–7i) with a series of quinuclidines in 80 mol% H2O/20 mol% DMSO at 25.0 ± 0.1 °C. The Brønsted‐type plot for the reactions of 7a–7i with quinuclidine is linear with β lg = −0.80. The Yukawa‐Tsuno plot exhibits an excellent linear correlation with ρY = 2.37 and r = 0.52, indicating that a negative charge develops partially on the O atom of the leaving group in the rate‐determining transition state (TS). The Brønsted‐type plot for the reactions of 2‐chloro‐4‐nitrophenyl picolinate (7a) with a series of quinuclidines is also linear with β nuc = 0.83. Thus, it was concluded that the reactions proceed through a stepwise mechanism, in which expulsion of the leaving group occurs in the rate‐determining step. Comparison of the current kinetic data with those reported previously for the corresponding reactions with piperidine revealed that quinuclidine is ca. 102‐fold less reactive than piperidine. This is in contrast to the reports that quinuclidines are more reactive than isobasic secondary amines toward diaryl carbonates and related esters. Effects of amine nature on reactivity and TS structures are discussed.

Discovery of novel α7 nicotinic acetylcholine receptor ligands via pharmacophoric and docking studies of benzylidene anabaseine analogs

Based on pharmacophore elucidation and docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR, novel spirodiazepine and spiroimidazoline quinuclidine series have been designed. Binding studies revealed that some of hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype in comparison with most potent metabolite of GTS-21, 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine. Hydrophobicity and rigidity of the ligand also contribute into its binding affinity. We also describe alternative pharmacophoric features equidistant from the carbonyl oxygen atom of the conserved Trp-148 of the principal face, which may be exploited to further design diverse focused libraries targeting the α7 nAChR.

Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): Application to the design of related α7 selective ligands

AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the α7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH2 functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-π interactions. The use of AChBPs structure as a surrogate to predict binding affinity to α7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a α7 homology model, Bt or Ac crystal structure is used.

Discovery of Novel 1-Azoniabicyclo[2.2.2]octane Muscarinic Acetylcholine Receptor Antagonists

A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.

Preparation of novel azabicyclic amines and α7 nicotinic acetylcholine receptor activity of derived aryl amides

Abstractmagnified imageThree new azabicyclic amines, namely exo‐3‐amino‐1‐azabicyclo[3.2.1]octane, 3‐amino‐1‐azabicyclo‐[3.2.2]nonane and exo‐6‐amino‐8‐azabicyclo[3.2.1]octane, have been designed and prepared as isosteres of 3‐aminoquinuclidine. Aryl amides derived from each series were prepared and tested in an α7 nicotinic acetylcholine receptor assay as part of a drug discovery program to treat the cognitive deficits in schizophrenia. All new amides showed significant α7 nAChR activity and one series displayed potent α7 activity equal to the quinuclidine series.

Synthesis and evaluation of phenylcarbamate derivatives as ligands for nicotinic acetylcholine receptors

Phenylcarbamate derivatives were synthesized and evaluated in radioligand binding assays for different nicotinic acetylcholine receptor (nAChR) subtypes. Carbamate derivatives bearing a pyrrolidine or piperidine moiety 8–20 exhibited much lower affinity for α7∗ nAChR than the analogues in the quinuclidine series 21–25, although the same structural elements are present. Furthermore, in contrast to the quinuclidine analogues 21–25, all (S)-pyrrolidine derivatives 8–12 and the piperidine analogues 15 and 16 exhibited higher affinities for α4β2∗ nAChR.

Kinetics and mechanism of the aminolysis of 4-methylphenyl and 4-chlorophenyl 4-nitrophenyl carbonates in aqueous ethanol.

Reactions of 4-methylphenyl 4-nitrophenyl carbonate (MPNPC) and 4-chlorophenyl 4-nitrophenyl carbonate (ClPNPC) with a series of quinuclidines (QUIN) and the latter carbonate with a series of secondary alicyclic amines (SAA) are subjected to a kinetic investigation in 44 wt % ethanol-water, at 25.0 degrees C and an ionic strength of 0.2 M. The reactions were followed spectrophotometrically at 330 or 400 nm (4-nitrophenol or 4-nitrophenoxide anion appearance, respectively). Under excess amine, pseudo-first-order rate coefficients (k(obsd)) are found. For all these reactions, plots of k(obsd) vs free amine concentration at constant pH are linear, the slope (k(N)) being independent of pH. The Brönsted-type plots (log k(N) vs pK(a) of the conjugate acids of the amines) for the reactions of the series of QUIN with MPNPC and ClPNPC are linear with slopes (beta(N)) 0.88 and 0.87, respectively, which are explained by a stepwise process where breakdown of a zwitterionic tetrahedral intermediate (T(+/-)) to products is rate limiting. The Brönsted-type plot for the reactions of the series of SAA with ClPNPC is biphasic with slopes beta(1) = 0.2 (high pK(a) region) and beta(2) = 0.9 (low pK(a) region) and a curvature center at pK(a)(0) = 10.6. This plot is in accordance with a stepwise mechanism through T(+/-) and a change in the rate-determining step, from T(+/-) breakdown to T(+/-) formation as the basicity of the SAA increases. Two conclusions arise from these results: (i) QUIN are better leaving groups from T(+/-) than isobasic SAA, and (ii) the non-leaving group effect on k(N) for these reactions is small, since beta(nlg) ranges from -0.2 to - 0.3. From these values, it is deduced that ClPNPC is ca. 70% more reactive than MPNPC toward SAA and QUIN, when expulsion of the leaving group from T(+/-) is the rate determining step.

Change in rate-determining step in an E1cB mechanism during aminolysis of sulfamate esters in acetonitrile.

The kinetics of the reactions of the nitrogen-sulfur(VI) esters 4-nitrophenyl N-methylsulfamate (NPMS) with a series of pyridines and a series of alicyclic amines and of 4-nitrophenyl N-benzylsulfamate (NPBS) with pyridines, alicyclic amines, and a series of quinuclidines have been investigated in acetonitrile (ACN) in the presence of excess amine at various temperatures. Pseudo-first-order rate constants (k(obsd)) have been obtained by monitoring the release of 4-nitrophenol/4-nitrophenoxide. From the slope of a plot of k(obsd) vs [amine], second-order rate constants (k'(2)) have been obtained for the pyridinolysis of NPMS, and a Brønsted plot of log k'(2) vs pK(a) of pyridine gave a straight line with beta = 0.45. However, aminolysis with alicyclic amines of NPMS gave a biphasic Brønsted plot (beta(1) = 0.6, beta(2) approximately equal to 0). Pyridinolysis and aminolysis with alicyclic amines and quinuclidines of NPBS also gave similar biphasic Brønsted plots. This biphasic behavior has been explained in terms of a mechanistic change within the E1cB mechanism from an (E1cB)(irrev) (less basic amines) to an (E1cB)(rev) (more basic amines), and the change occurs at approximately the pK(a)'s (in ACN) of NPMS (17.94) and NPBS (17.68). The straight line Brønsted plot for NPMS with pyridines occurs because the later bases are not strong enough to substantially remove the substrate proton and initiate the mechanistic change observed in the reaction of NPMS with the strong alicyclic amines and quinuclidines. An entropy study supports the change from a bimolecular to a unimolecular mechanism. This is the first clear demonstration of this E1cB mechanistic changeover involving a nitrogen acid substrate.

Design and pharmacology of quinuclidine derivatives as M 2-selective muscarinic receptor ligands

In our search for M 2-selective muscarinic receptor antagonists, we synthesized 1,3-disubstituted indenes. The effects of different basic moieties with regard to binding and selectivity towards the five distinct muscarinic receptor subtypes were investigated. The results show that the quinuclidine series afforded the most promising compounds in terms of both receptor affinity and M 2-subtype selectivity.

Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: optimization from lipid profiles.

Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.

39 Nicotinic agonists and learning in rabbits: Implications for Alzheimer's disease

Based on pharmacophore elucidation and docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR, novel spirodiazepine and spiroimidazoline quinuclidine series have been designed. Binding studies revealed that some of hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype in comparison with most potent metabolite of GTS-21, 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine. Hydrophobicity and rigidity of the ligand also contribute into its binding affinity. We also describe alternative pharmacophoric features equidistant from the carbonyl oxygen atom of the conserved Trp-148 of the principal face, which may be exploited to further design diverse focused libraries targeting the α7 nAChR.

Characterization of the interaction of N-acyl-L-tryptophan benzyl ester neurokinin antagonists with the human neurokinin-1 receptor.

We have recently shown that a series of N-acyl-L-tryptophan benzyl esters are potent substance P antagonists (Macleod, A. M., Merchant, K. J., Cascieri, M. A., Sadowski, S., Ber, E., Swain, C. J., and Baker, R. (1993) J. Med Chem. 14, 2044-2045). We now report the detailed characterization of the interaction of N-acetyl-L-tryptophan-3,5-bistrifluoromethyl benzyl ester (L-732,138) with the human neurokinin-1 (NK-1) receptor. L-732,138 inhibits the binding of 125I-substance P to the cloned human NK1 receptor expressed in Chinese hamster ovary cells with an IC50 of 2.3 +/- 0.7 nM. In contrast, it has 200-fold lower affinity for the cloned rat NK-1 receptor and has > 1000-fold lower affinity for the human NK-2 and NK-3 receptors. L-732,138 acts as a competitive antagonist of substance P, as shown by functional Schild analysis of the inhibition of substance P-induced inositol phosphate synthesis, by kinetic analysis of the dissociation rate, and by thermodynamic analysis of the equilibrium binding of 125I-substance P to the NK-1 receptor. L-732,138 also competitively inhibits the binding of the quinuclidine amine antagonist, [125I]L-703,606, to the receptor. The compound has 230- and 10-fold reduced affinity for mutant NK-1 receptors in which histidine 265 or histidine 197, respectively, are replaced with alanine. We have previously shown that these residues play key roles in the binding of quinuclidine antagonists to the NK-1 receptor. These results suggest that the tryptophan and quinuclidine series of NK-1 antagonists bind to similar binding sites on the human NK-1 receptor.

The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]-octan-3-amine as a novel, nonpeptide substance P antagonisst.

We describe the structure-activity relationship development of a series of quinuclidines which culminated in the first potent, selective, nonpeptide substance P (SP) antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine, 3 (CP-96,345). Compound 3 is a potent displacer of [3H]SP binding in human IM-9 cells and blocks SP-induced and capsaicin-induced plasma extravasation, as well as SP-induced salivation in the rat in vivo. This compound may both help to further our understanding of the interactions of small molecules with peptide receptors and serve to evaluate the therapeutic potential of a SP antagonist.

A novel series of non‐quaternary oxadiazoles acting as full agonists at muscarinic receptors

1 A novel series of non-quaternary oxadiazole-based muscarinic agonists demonstrated high affinity for muscarinic receptors. 2. These agonists possessed high efficacy in the nanomolar range at muscarinic receptors in the superior cervical ganglion, atrium and ileum but did not show selectivity across the tissue preparations. 3. Two amino oxadiazoles, one from a quinuclidine series (L-660,863) and one from a 1-azanorbornane series (L-670,207) possessed a high ratio of potency for displacing the binding of [3H]-N-methyl-scopolamine ([3H]-NMS) to potency for displacing the agonist [3H]-oxotremorine-M cortex. 4. The two azanorbornane derivatives L-670,548 and L-670,207 stimulated the turnover of phosphatidylinositol in the cortex with a potency higher than that obtained with any other known muscarinic agonist (ED50 0.26 and 0.18 microM respectively). 5. The maximum response obtained with L-670,207 was greater than that observed for carbachol but was comparable to that of the natural ligand acetylcholine. 6. These oxadiazole muscarinic agonists are among the most potent and efficacious non-quaternary muscarinic agonists ever described.

Studies in the quinuclidine series in a search for new medicinal preparations (review)

Studies in the quinuclidine series in a search for new medicinal preparations (review)

Synthesis and properties of N-oxides of quinuclidine and its derivatives

It was shown that quinuclidine N-oxide, similarly to tertiary amines and quaternary salts of the quinuclidine series, displays thermal stability to ring opening and undergoes only deoxygenation upon pyrolysis.

Synthesis and pharmacological investigation of unsymmetricalα,ω-bisquaternary salts of the quinuclidine series

Synthesis and pharmacological investigation of unsymmetricalα,ω-bisquaternary salts of the quinuclidine series