Adeboye Adejare

Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.

NMDA Receptor Antagonists for Treatment of Depression

Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery.

Preparation and analytical characterization of 1-(1-phenylcyclohexyl)piperidine (PCP) and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) analogues

Classic examples of psychoactive arylcycloalkylamines include ketamine and 1-(1-phenylcyclohexyl)piperidine (PCP) and many others serve as important structural templates for neuropharmacological research. The recent emergence of PCP analogues that can be obtained from internet retailers requires the implementation of appropriate monitoring strategies for harm reduction purposes. Access to analytical data plays a key part when encountering these substances, especially if reference material is not available. The present study describes the synthesis of three substituted 1-(1-phenylcyclohexyl)piperidines, (3-MeO-, 4-MeO- and 3-Me-PCP) and three substituted 1-(1-phenylcyclohexyl)pyrrolidine analogues (3-MeO-, 4-MeO- and 3-Me-PCPy). Analytical characterizations of all six arylcyclohexylamines and their primary 1-phenylcyclohexanamine intermediates included gas chromatography ion trap electron- and chemical ionization and high resolution mass spectrometry, liquid chromatography electrospray hybrid triple-quadrupole linear ion trap tandem mass spectrometry, infrared, diode array detection and (1) H and (13) C nuclear magnetic resonance (NMR) spectroscopy. Solvent (CDCl3 vs. d6 -DMSO) and protonation effects (free bases vs hydrochloride salts) were studied in order to investigate the impact on shifts and splitting patterns, for example, when attempting to assign separate axial and equatorial proton chemical shifts of NMR spectra. Differentiation between the isomeric 3-MeO-/4-MeO-PCP and PCPy analogues was feasible under mass spectral conditions. Gas chromatography analysis appeared to induce notable degradation of the 4-MeO-substituted analytes, especially when dealing with the HCl salts which led to the detection of the substituted 1-phenylcyclohex-1-ene nucleus. This phenomenon was observed to be less pronounced with the 3-MeO isomers, possibly due to the resonance properties of the para-methoxy group followed by more facile elimination of the amine.

Fluorinated molecules in the diagnosis and treatment of neurodegenerative diseases

The use of fluorinated molecules as drugs and imaging agents for CNS disorders has been studied extensively over the years. Incorporating a fluorine atom into the structure of a drug changes its physiochemical properties and can thereby lead to much more desirable pharmacokinetic and pharmacodynamic properties. This change can help to facilitate blood-brain barrier permeability, which is a critical matter for drugs intended for CNS activities. Fluorine incorporation into structures of drugs for the treatment of neurodegenerative diseases has been an attractive field for drug discovery. Such incorporation can greatly influence the physicochemical properties, metabolic stability and receptor binding affinity of the resulting molecule. Some studies have shown that when a proton was substituted with fluorine, the binding or inhibitory potency was greatly increased. The fluorine-18 isotope, (18)F, is utilized in detection and diagnosis of neurodegenerative diseases, whereas (19)F compounds are used in the treatment of these diseases and in MRI. (18)F is widely used in PET imaging because it offers the advantage of a longer half-life compared with other radionuclides. It is used for imaging various receptors and transporters that have been linked to neurodegenerative diseases, such as Alzheimers disease, Parkinsons disease, Huntingtons disease and multiple system atrophy. Fluorine plays an important role in the diagnosis and treatment of many CNS diseases, including neurodegenerative disorders. The use of fluorine in the diagnosis and treatment of neurodegenerative diseases, such as Alzheimers disease and Parkinsons disease, will be discussed in this review.

A Randomized Crossover Study Investigating the Influence of Ranitidine or Omeprazole on the Pharmacokinetics of Cephalexin Monohydrate

Limited data characterize pharmacokinetic interactions between cephalexin and ranitidine, and no data exist for an interaction with proton pump inhibitors. The purpose of this study was to investigate the effects of ranitidine or omeprazole administration on the pharmacokinetics and pharmacodynamics of cephalexin. A randomized single‐ and multiple‐dose crossover study was conducted in healthy subjects ingesting cephalexin before and after steady‐state administration of ranitidine or omeprazole. Time‐concentration profiles were determined and pharmacokinetic parameters were characterized using noncompartmental methods. Pharmacokinetic data were analyzed in accordance with the two 1‐sided test for bioequivalence. The percentage of time that serum concentrations remain above the MIC90 during the dosing interval (T < MIC90) for Streptococcus pyogenes and Staphylococcus aureus associated with the pharmacokinetic profiles was calculated. The coadministration of cephalexin with ranitidine or omeprazole resulted in relatively minor changes in Cmax, AUC, t1/2, or CL/F. tmax was significantly prolonged when cephalexin was administered with ranitidine or omeprazole. Suboptimal T > MIC90 was observed for cephalexin irrespective of acid suppression. Delay in absorption of cephalexin resulted in a decrease in the percentage of T > MIC90 for certain acid‐suppressive regimens and pathogen combinations. With the exception of an increase in tmax, there were no significant pharmacokinetic interactions between cephalexin and ranitidine or omeprazole. Delayed tmax associated with acid suppression may result in a diminished T > MIC90.

Developing selective histone deacetylases (HDACs) inhibitors through ebselen and analogs

Histone deacetylases (HDACs) are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors. In an effort to discover existing scaffolds with HDAC inhibitory activity, we screened a drug library approved by the US Food and Drug Administration and a National Institutes of Health Clinical Collection compound library in HDAC enzymatic assays. Ebselen, a clinical safe compound, was identified as a weak inhibitor of several HDACs, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 with half maximal inhibitory concentrations approximately single digit of µM. Two ebselen analogs, ebselen oxide and ebsulfur (a diselenide analog of ebselen), also inhibited these HDACs, however with improved potencies on HDAC8. Benzisothiazol, the core structure of ebsulfur, specifically inhibited HDAC6 at a single digit of µM but had no inhibition on other HDACs. Further efforts on structure–activity relationship based on the core structure of ebsulfur led to the discovery of a novel class of potent and selective HDAC6 inhibitors with RBC-2008 as the lead compound with single-digit nM potency. This class of histone deacetylase inhibitor features a novel pharmacophore with an ebsulfur scaffold selectively targeting HDAC6. Consistent with its inhibition on HDAC6, RBC-2008 significantly increased the acetylation levels of α-tubulin in PC-3 cells. Furthermore, treatment with these compounds led to cell death of multiple tumor cell lines in a dose-dependent manner. These results demonstrated that ebselen and ebsulfur analogs are inhibitors of HDACs, supporting further preclinical development of this class of compounds for potential therapeutic applications.

Toxicity Studies on Novel N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors

Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic effects of the compounds as compared with memantine, an NMDA receptor antagonist that is FDA approved for treatment of Alzheimer’s disease, by testing these compounds on two cell lines: MDCK (to mimic blood brain barrier) and N2a (a neuronal cell line). The compounds showed toxicity profiles similar to those of memantine i.e., dose dependence above 100 μM and IC50 values above 150 μM for each cell line. It is known that the serum level of memantine under therapeutic conditions in patients is about 1 µM, indicting these compounds could have acceptable therapeutic indexes. 2-Phenyl-N-(2-(piperidin-1-yl) ethyl)bicyclo[2.2.1]heptan-2-amine (5a) was found to possess acceptable toxicity profiles in both cell lines. Interestingly, this was the compound identified as a good lead in our previous studies based on binding and anticonvulsant (MES) activity studies. It has thus emerged as an excellent lead compound for further studies.

Syntheses and in vitro anticancer properties of novel radiosensitizers.

Series of 4‐(ethylsulfonyl)‐1‐halogen‐2‐nitrobenzene (3a–e) and 1‐(4‐halogen‐3‐nitrophenyl) propan‐1‐one (5a–d) analogs designed as novel radiosensitizers using bromonitropropiophenone and bromonitrobenzonitrile as lead compounds were synthesized. The anticancer activities of the compounds were evaluated in vitro using human prostate cancer (DU‐145) and breast cancer (MCF‐7) cell lines and the MTT assay. From the series, six compounds (3b–e, 5b–c) exhibited potent growth inhibitory effects against both cell lines. The most active, compound 3d, is an iodosulfone and is significantly more potent than the lead compound 5c at 10 μm. Compounds were then compared with doxorubicin, a clinically used anticancer compound for breast and prostate cancers. Our most active compound 3d is more effective than doxorubicin at the dose level of 10 μm at 3 days after radiation, cell viabilities of 18%, 13% compared to 87%, 94% against MCF‐7, and 15%, 20% compared to 60%, 75% against DU‐145 without and with radiation, respectively. At 10 μm, compound 5c had no effects as compared to control, whereas compound 3d reduced DU‐145 cell viability to 16% and that of MCF‐7 cells to 9% even at 5 days after radiation. These results are very encouraging. Future studies include testing the compounds in vivo with and without radiation.

Receptor Targets in Alzheimer’s Disease Drug Discovery

A high number of receptor targets have been investigated as potential therapeutic targets in Alzheimer’s disease (AD) treatment. These include binding sites of G protein-coupled receptors, enzymes, ionotropic receptors, and hormonal receptors. This chapter presents a brief overview of some of these receptor sites with respect to drug discovery in AD as well as some of the most recent drugs that target them. Priority was given to receptors investigated within the last decade that have advanced to high preclinical or clinical status in the drug discovery and development continuum. In addition, newer receptor-based strategies such as polypharmacological approaches are briefly discussed.

Syntheses and pharmacological evaluations of novel N-substituted bicyclo-heptane-2-amines at N-methyl-D-aspartate receptors.

Several novel norcamphor (bicycloheptane)‐based compounds were designed and synthesized as non‐competitive N‐methyl‐d‐aspartate receptor antagonists at the phencyclidine binding sites. The heterocyclic ring was also varied to examine piperidine, pyrrolidine, and morpholine groups. We examined pharmacological activities of these compounds in vitro (binding studies) and in vivo (maximal electroshock test). Pharmacological evaluations revealed one of the compounds, 5a, to be a good lead, exhibiting moderate binding at N‐methyl‐d‐aspartate receptors (IC50 = 7.86 μm; Ki = 5.28 μm), maximal electroshock neuroprotection activity at 100 mg/kg and acceptable toxicity profile.