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The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.

ABSTRACT: 3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the ?4?2(?) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for ?4?2(?) nAChR. All evaluated compounds are partial agonists or antagonists at ?4?2(?), with reduced or no effects on ?3?4(?) with the exception of compound 15 (agonist), and reduced or no effect at ?7 and muscle subtypes.

SUBMITTER: Eibl C

PROVIDER: S-EPMC4519236 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.

Eibl Christoph C Munoz Lenka L Tomassoli Isabelle I Stokes Clare C Papke Roger L RL Gündisch Daniela D

Bioorganic & medicinal chemistry 20131005 23

3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the ...[more]

PMID: 24145137

Similar Datasets

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: the influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents.

Project description:3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for ?4?2(?) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for ?4?2(?) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.

| S-EPMC4519239 | biostudies-literature

Crystal structures and supra-molecular features of 9,9-dimethyl-3,7-di-aza-bicyclo-[3.3.1]nonane-2,4,6,8-tetra-one, 3,7-di-aza-spiro-[bi-cyclo-[3.3.1]nonane-9,1'-cyclo-penta-ne]-2,4,6,8-tetra-one and 9-methyl-9-phenyl-3,7-di-aza-bicyclo-[3.3.1]nonane-2,4,6,8-tetra-one di-methyl-formamide monosolvate.

Project description:Compounds (I), C9H10N2O4, (II), C11H12N2O4, and (III), C14H12N2O4·C3H7NO represent 9,9-disubstituted-3,7-di-aza-bicyclo-[3.3.1]nonane-2,4,6,8-tetra-one deriv-atives with very similar mol-ecular geometries for the bicyclic framework: the dihedral angle between the planes of the imide groups is 74.87 (6), 73.86 (3) and 74.83 (6)° in (I)-(III), respectively. The dimethyl derivative (I) is positioned on a crystallographic twofold axis and its overall geometry deviates only slightly from idealized C2v symmetry. The spiro-cyclo-pentane derivative (II) and the phen-yl/methyl analog (III) retain only inter-nal Cs symmetry, which in the case of (II) coincides with crystallographic mirror symmetry. The cyclo-pentane moiety in (II) adopts an envelope conformation, with the spiro C atom deviating from the mean plane of the rest of the ring by 0.548 (2) Å. In compound (III), an N-H⋯O hydrogen bond is formed with the di-methyl-formamide solvent mol-ecule. In the crystal, both (I) and (II) form similar zigzag hydrogen-bonded ribbons through double inter-molecular N-H⋯O hydrogen bonds. However, whereas in (I) the ribbons are formed by two trans-arranged O=C-N-H amide fragments, the amide fragments are cis-positioned in (II). The formation of ribbons in (III) is apparently disrupted by participation of one of its N-H groups in hydrogen bonding with the solvent mol-ecule. As a result, the mol-ecules of (III) form zigzag chains rather than the ribbons through inter-molecular N-H⋯O hydrogen bonds. The crystal of (I) was a pseudo-merohedral twin.

| S-EPMC5499299 | biostudies-literature

Synthesis and hLDH Inhibitory Activity of Analogues to Natural Products with 2,8-Dioxabicyclo[3.3.1]nonane Scaffold

Project description:Human lactate dehydrogenase (hLDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, hLDHA and hLDHB are the predominant ones. In the last few years, hLDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. hLDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new hLDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives (42–70) by reaction between flavylium salts (27–35) and several nucleophiles (36–41). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC50 values lower than 10 µM against hLDHA and better activity than our previously reported compound 2. In order to know the selectivity of the synthesized compounds against hLDHA, their hLDHB inhibitory activities were also measured. In particular, compounds 58, 62a, 65b, and 68a have shown the lowest IC50 values against hLDHA (3.6–12.0 µM) and the highest selectivity rate (>25). Structure–activity relationships have been deduced. Kinetic studies using a Lineweaver–Burk double-reciprocal plot have indicated that both enantiomers of 68a and 68b behave as noncompetitive inhibitors on hLDHA enzyme.

| S-EPMC10298284 | biostudies-literature

Tri-cyclo-[3.3.1.0(3,7)]nonane-3,7-diyl bis-(4-methyl-benzene-sulfonate).

Project description:The title compound, C23H26O6S2 was synthesized by esterification of tri-cyclo-[3.3.1.0(3,7)]nonane-3,7-diol with p-toluene-sulfonyl chloride. The mol-ecule has symmetry 2 and is situated on site 4e. The C-C bond length between the quartenary C atoms is 1.598?(2)?Å, which is considerably longer than other C-C bonds in the mol-ecule. There are C-H?O inter-actions present in the structure. As a consequence, the packing of the molecule (viewed along [100]) appears as chains where the molecules run parallel, but each chain has the opposite direction to the neighboring ones.

| S-EPMC3884498 | biostudies-literature

2-Isobutyl-2-phosphabicyclo-[3.3.1]nonane 2-selenide.

Project description:The title compound, C(12)H(23)PSe, represents the first structure of a phosphine containing the bicyclic 2-phospha-bicyclo-[3.3.1]nonane (VCH) unit. It contains two chiral centres per mol-ecule which can be either R,R- or S,S and crystallizes as a centrosymmetric, racemic micture of the enanti-omers. The P-Se bond distance of 2.1360?(16)?Å is typical for these compounds. The Tolman cone angle (2.28?Å from P) was calculated as 163°, and the effective cone angle (using the crystallographically determined P-Se bond distance) is 168°.

| S-EPMC2968513 | biostudies-literature

rac-4,8-Divinyl-bicyclo-[3.3.1]nonane-2,6-dione.

Project description:The title compound, C(13)H(16)O(2), is a chiral bicyclic structure composed of two fused cyclo-hexa-ne rings possessing both boat and chair conformations. The mol-ecules are packed in enantio-pure columns which are pairwise linked forming an overall racemic solid; within the column pairs the packing is governed by weak dipole-dipole inter-actions stemming from stacked carbonyl functionalities (CO(centroid)-CO(centroid) distance = 3.290 Å).

| S-EPMC2969760 | biostudies-literature

Tricyclo-[3.3.1.0]nonane-3,7-diyl bis-(methane-sulfonate).

Project description:The crystal structure of the title compound, C(11)H(18)O(6)S(2), was determined to investigate the effect of the eclipsed mesyl groups on the bond length of the vicinal quaternary C atoms. The two quaternary C atoms of the noradamantane skeleton and the two O atoms to which they are connected all located essentially in the same plane [maximum deviation 0.01?Å], resulting in an eclipsing conformation of the C-O bonds. The C-C bond of the quaternary C atoms is 1.597?(3)?Å is considerably longer than the other C-C bonds of the mol-ecule.

| S-EPMC2979816 | biostudies-other

3-Nitroso-2,4,6,8-tetra-phenyl-3,7-diaza-bicyclo-[3.3.1]nonan-9-one.

Project description:In the title compound, C(31)H(27)N(3)O(2), the two piperidine rings fused to each other each adopt a slightly distorted chair conformation. The phenyl rings on the N-unsubstituted piperidine ring occupy an equatorial position, while those on the N-nitroso-substituted piperidine ring are in axial positions. The NO group is approximately coplanar with the piperidine ring with a maximum deviation of 0.048?(4)?Å. The dihedral angles between the mean planes of the axially and equatorially oriented phenyl rings are 27.7?(1) and 31.9?(1)°, respectively. Mol-ecular packing is stabilized by weak inter-molecular C-H?O and C-H?? inter-actions.

| S-EPMC3152129 | biostudies-literature

Disclosure of cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor.

Project description:Cholesterol influences ion-channel function, distribution and clustering in the membrane, endocytosis, and exocytic sorting of the nicotinic acetylcholine receptor (AChR). We report the occurrence of a cholesterol recognition motif, here coined "CARC", in the transmembrane regions of AChR subunits that bear extensive contact with the surrounding lipid, and are thus optimally suited to convey cholesterol-mediated signaling from the latter. Three cholesterol molecules could be docked on the transmembrane segments of each AChR subunit, rendering a total of 15 cholesterol molecules per AChR molecule. The CARC motifs contribute each with an energy of interaction between 35 and 52?kJ.mol(-1), adding up to a total of about 200?kJ.mol(-1) per receptor molecule, i.e. ?40% of the lipid solvation free energy/ AChR molecule. The CARC motif is remarkably conserved along the phylogenetic scale, from prokaryotes to human, suggesting that it could be responsible for some of the above structural/functional properties of the AChR.

| S-EPMC3216556 | biostudies-literature

(1R*,2R*,4S*,5R*,6R*,8S*)-4,8-Dimethyl-2,6-diphenyl-bicyclo-[3.3.1]nonane-2,6-diol.

Project description:The racemic title compound, C(23)H(28)O(2), crystallizes in the space group C2/c as a layered structure in which a centrosymmetric three hydrogen bond sequence links four molecules. Both hydroxy groups are involved in this arrangement, but they differ in that one participates in two hydrogen bonds while the other takes part in only one. Between layers, the aromatic rings take part in edge-face interactions [shortest C-H⋯C distances 3.04, 3.10 and 3.12 Å and angle between normal to planes 86.7(2)°], forming a centrosymmetric dimer. The lattice is further stabilized by C-H⋯π interactions involving both methyl (shortest C⋯C 3.82 and 3.97 Å) and methylene (shortest C⋯C 3.60 Å) groups.

| S-EPMC2968924 | biostudies-literature

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