7β-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues.

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7β-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7β-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7β-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7β-methyl orvinol analogues.

The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent κ-Opioid Agonistic Activities.

To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group.

Meserine, a novel carbamate AChE inhibitor, ameliorates scopolamine-induced dementia and alleviates amyloidogenesis of APP/PS1 transgenic mice.

Aims: To investigate whether Meserine, a novel phenylcarbamate derivative of (-)-meptazinol, possesses beneficial activities against cholinergic deficiency and amyloidogenesis, the two major pathological characteristics of Alzheimer's disease (AD).

Methods: Ellman's assay and Morris water maze were used to detect acetylcholinesterase (AChE) activity and evaluate spatial learning and memory ability, respectively. Both high content screening and Western blotting were carried out to detect β-amyloid precursor protein (APP), while RT-PCR and ELISA were conducted to detect APP-mRNA and β-amyloid peptide (Aβ).

Bis(9)-(-)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder which is characterized by the progressive deterioration of cognition and the emergence of behavioral and psychological symptoms in aging patients. Given that the clinical effectiveness of acetylcholinesterase inhibitors (AChEIs) has still been questioned due to dubious disease-modifying effects, the multi-target directed ligand (MTDL) design has become an emerging strategy for developing new drugs for AD treatment. Bis(9)-(-)-nor-meptazinol (Bis-Mep) was firstly reported by us as a novel MTDL for both potent cholinesterase and amyloid-β aggregation inhibition.

Determination of Bis(9)-(-)-Meptazinol, a bis-ligand for Alzheimer's disease, in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetics study.

A rapid, simple and sensitive LC-MS/MS method was developed and validated for the determination of Bis(9)-(-)-Meptazinol (B9M) in rat plasma. Protein precipitation method was used for sample preparation, using five volumes of methanol as the precipitation agent. The analytes were separated by a Zorbax Extend-C18 column with the mobile phase of methanol-water (containing 5mM ammonium formate, pH 9.

3-[(3S)-3-Ethyl-1-methyl-azepan-3-yl]phenyl N-(4-fluoro-phen-yl)carbamate.

The asymmetric unit of the title compound, C(22)H(27)FN(2)O(2), a (-)-S-meptazinol derivative, contains two mol-ecules. The azepane ring adopts a similar twist chair form in both mol-ecules, while the dihedral angles between the two benzene rings are 88.17 (14) and 89.

(3S,4R)-3-Ethyl-4-hydr-oxy-3-(3-methoxy-phen-yl)-1-methyl-azepanium (2R,3R)-2,3-bis-(benzo-yloxy)-3-carboxy-propionate.

The crystal structure of the title compound, C(16)H(26)NO(2) (+)·C(18)H(13)O(8) (-), is stabilized by an extensive network of classical N-H⋯O and O-H⋯O hydrogen bonding. The crystal structure also shows an ammonium-driven diastereo-isomerism.

Highly selective and potent mu opioid ligands by unexpected substituent on morphine skeleton.

Unexpected substituent on the well-known morphine skeleton is described to be account for highly selective and potent mu opioid ligands, which is strongly connected to substituted aromatic groups on this omitted 8alpha-position.

Novel piperazine derivative PMS1339 exhibits tri-functional properties and cognitive improvement in mice.

Amyloid-beta-induced neuroinflammation plays a central role in the extensive loss of cholinergic neurons and cognitive decline in Alzheimer's disease. The acetylcholinesterase (AChE) inhibitors are the first class of drugs used to enhance surviving cholinergic activities. However, their limited effectiveness following long-term treatment raises a need for new multi-target therapies.

2-Methyl-1,2,3,4-tetra-hydro-isoquinolin-6-yl N-phenyl-carbamate.

In the mol-ecule of the title compound, C(17)H(18)N(2)O(2), the piperidine ring adopts a half-chair form. The two benzene rings are individually planar and make a dihedral angle of 53.90°.

1-Ethyl-4-hydr-oxy-9-aza-tricyclo-[7.4.1.0]tetra-deca-2,4,6-trien-8-one.

In the mol-ecule of the title compound, C(15)H(19)NO(2), the six-membered dihydro-pyridinone ring assumes a screw-boat conformation. In the crystal structure, mol-ecules are linked via O-H⋯O hydrogen bonding between hydr-oxy and carbonyl groups, forming supra-molecular chains along the a axis.

(E)-6-Meth-oxy-9-methyl-1,2,3,4-tetra-hydro-9H-carbazol-4-one oxime.

The title compound, C(14)H(16)N(2)O(2), is dimerized by inversion-related inter-molecular O-H⋯O and O-H⋯N hydrogen bonding. There is also an intra-molecular C-H⋯N bond, resulting in a six-membered ring.

(3S,4S)-3-Ethyl-4-hydr-oxy-3-(3-methoxy-phen-yl)-1-methyl-azepan-1-ium d-tartrate dihydrate.

In the title compound, C(16)H(26)NO(2) (+)·C(4)H(5)O(6) (-)·2H(2)O, a meptaz-inol derivative, three C atoms of the azepane ring are disordered over two positions, with site-occupancy factors of 0.80 and 0.20; the major disorder component adopts a twist-chair conformation, while the minor component has a chair conformation.

Conformational re-analysis of (+)-meptazinol: an opioid with mixed analgesic pharmacophores.

Aim: To further investigate the analgesic pharmacophore of (+)-meptazinol.

Methods: Two different opioid pharmacophores, Pharm-I and Pharm-II, were established from structures of nine typical opiates and meperidine by using molecular modeling approaches according to their different structure activity relationship properties. They were further validated by a set of conformationally constrained arylpiperidines.

3D-QSAR studies of orvinol analogs as kappa-opioid agonists.

Orvinols are potent analgesics that target opioid receptors. However, their analgesic mechanism remains unclear and no significant preference for subtype opioid receptor has been achieved. In order to find new orvinols that target the kappa-receptor, comparative 3D-QSAR studies were performed on 26 orvinol analogs using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).

Investigation of the binding mode of (-)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method.

Molecular docking has been performed to investigate the binding mode of (-)-meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD<1.

QSAR study of 4-phenylpiperidine derivatives as mu opioid agonists by neural network method.

A nonlinear QSAR study was conducted on a series of 4-phenylpiperidine derivatives (4PPs) acting as mu opioid agonists by three-layer back-propagation neural network (NN) method. At first a variety of molecular descriptors were calculated and then selected with two-stage least squares combining partial least squares (PLS) method. The selected four molecular descriptors, out of 292 ones, were correlated with the known analgesic activities of 38 4PPs by NN method.

Molecular modeling and 3D-QSAR studies of indolomorphinan derivatives as kappa opioid antagonists.

Molecular modeling and 3D-QSAR studies were performed on 31 indolomorphinan derivatives to evaluate their antagonistic behaviors on kappa opioid receptor and provide information for further modification of this kind of compounds. Best predictions were obtained with CoMFA standard model (q2 = 0.693, N = 4, r2 = 0.

Structural comparisons of meptazinol with opioid analgesics.

Aim: To investigate the mechanism of action of a potent analgesic, (+/-)-meptazinol.

Methods: The structures of meptazinol enantiomers were compared with opioid pharmacophore and tramadol.

Results: Neither enantiomer of meptazinol fitted any patterns among the opioid pharmacophore and tramadol, although they did share some structural and pharmacological similarities.

Antinociceptive effects of meptazinol and its isomers on carrageenan-induced thermal hyperalgesia in rats.

Using the latency of paw withdrawal (PWL) from a noxious thermal stimulus as a measure of hyperalgesia, the effects of i.p. injection of meptazinol and its isomers, 112824 and 112825, on carrageenan-induced thermal hyperalgesia were studied in awaked carrageenan-inflamed rats.

Inhibitory effect of intrathecal meptazinol on carrageenan-induced thermal hyperalgesia in rats.

The effect of meptazinol in the spinal cord on carrageenan-induced hyperalgesia was investigated. The latency of paw withdrawal (PWL) to a thermal stimulus was used as an index of inflammatory hyperalgesia in awake rats. Intrathecal (i.

[Binding characteristics of new synthesized opioid receptor ligands to cloned mu opioid receptors stably expressed in CHO cell].

Objective: To determine the affinity of new opioid receptor ligands to cloned mu opioid receptors stably expressed in CHO cell.

Methods: The binding characteristics of the opioid ligand [3H] diprenorphine (3H-dip) were studied by cellular biological techniques and radioligands binding in cloned mu opioid receptors stably expressed in CHO cells in saturation binding experiments, and were followed by competition binding experiments with a variety of new synthesized opioid receptor ligands.

Results: The Kd and Bmax of [3H] diprenorphine bound to mu receptors were 1.