Daniel J Canney

Daniel J Canney
Temple University | TU · Department of Pharmaceutical Sciences

Ph.D.
Selective 5-HT7 & Sigma-2 ligands with drug-like properties (in vitro ADME, PK data). Models for future studies welcome.

About

56
Publications
2,934
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478
Citations
Citations since 2017
11 Research Items
112 Citations
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Introduction
Working on evaluating our selective 5HT7 and Sigma-2 ligands in a variety of in vitro and in vivo assays to better understand their activity and how they might be useful as therapies for several diseases/disorders.
Additional affiliations
July 2020 - December 2020
Temple University
Position
  • Managing Director
Description
  • Research interests include the application of medicinal chemistry approaches to SAR studies involving novel ligands for pharmacologically important receptors (e.g., novel ligands for serotonergic and muscarinic receptors).
June 1993 - December 2020
Temple University, School of Pharmacy
Position
  • Professor (Associate)
Description
  • -Medicinal Chemistry II, 1995-present; -Medicinal Chemistry III, 2004-present; Emerging Therapeutic Targets, 2000-2002; Intro To Drug Design,1993-1999. Graduate-level: Advanced Med Chem I,1994-present; Pharmaceutical Analysis, 2001-present
March 1990 - June 1993
University of Pennsylvania
Position
  • Research Assistant Professor
Description
  • Synthesis of potential organ or receptor-specific imaging agents:(N2S2)-Tc-99m complexes as organ imaging agents and hexahydro-2H-benzo[a] quinolizine analogs as radioligands and/or SPECT imaging agents for CNS monoamine uptake sites.
Education
February 1987 - February 1990
Washington University in St. Louis
Field of study
  • Medicinal Chemistry
September 1980 - June 1986
Temple University
Field of study
  • Medicinal Chemistry

Publications

Publications (56)
Article
Full-text available
Sigma receptors (σ1 R and σ2 R) are pharmacologically characterized membrane-bound receptors that bind a wide range of chemical compounds. Alzheimer's disease, traumatic brain injury, schizophrenia, and neuropathic pain have all been associated with abnormal σ2 activity. The σ2 receptor has recently been identified as a potential therapeutic target...
Article
Full-text available
The sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein)). This protein has been linked to diseases and conditions such as Niemann-Pick disease, schizophrenia, neuropathic pain, traumatic brain injury, cancer, drug addiction, and Alzheimer’s disease. The therapeut...
Article
Full-text available
The sigma-2 (σ2) receptor, also known as the Transmembrane Protein 97 (TMEM97, and MAC30 (Meningioma-associated protein), has been linked to a number of conditions are disease states such as schizophrenia, cancer, Alzheimer’s disease, traumatic brain injury, and neuropathic pain. As part or our on-going effort identify novel σ2 ligands, we have ide...
Article
Full-text available
The sigma-2 (σ2) receptor was discovered nearly 40 years ago and was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein)). Aberrant σ2 activity has been linked to diseases and conditions such as schizophrenia, Alzheimer’s disease, neuropathic pain, traumatic brain injury, and cancer. The...
Preprint
Full-text available
Alzheimer’s disease is a major, unmet medical need that impacts 6 million people in the US alone. Therapeutic options are limited, and the root cause of this condition remains unclear. The Amyloid Hypothesis has been proposed as a means of explaining the formation of amyloid plaques in the brain of patient. The sigma-2 receptor was recently identif...
Preprint
Full-text available
The sigma-2 (σ2) receptor was discovered nearly 40 years ago and was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein). Aberrant σ2 activity has been linked to disease and conditions such as schizophrenia, Alzheimer’s disease, neuropathic pain, traumatic brain injury, and cancer. The ut...
Article
Full-text available
Nearly 40 years after the first disclosure of sigma receptors, the sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein). This macromolecule has been associated with a number of disease states such as schizophrenia, Alzheimer’s disease, neuropathic pain, traumatic...
Preprint
Full-text available
Nearly 40 years after the first disclosure of sigma receptors, the sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein). This macromolecule has been associated with a number of disease states such as schizophrenia, Alzheimer’s disease, neuropathic pain, traumatic...
Article
It is well documented that serotonin (5-HT) exerts its pharmacological effects through a series of 5-HT receptors. The most recently identified member of this family, 5-HT7, was first identified in 1993. Over the course of the last 25 years, this receptor has been the subject of intense investigation, and it has been demonstrated that 5-HT7 plays a...
Article
Full-text available
Background: A lead quinuclidine-based nicotinic ligand (EQA) served as the basis for the design of novel compounds. A new series of 3-substituted quinuclidines was designed, synthesized and evaluated as nicotinic ligands. Methods: The goal was to improve affinity for nicotinic receptors in the CNS. Interatomic distance calculations were performe...
Chapter
Our efforts in design and development of novel muscarinic acetylcholine receptor (mAChR) antagonists led to the development of a novel series of γ-butyrolactone derivatives. We were interested in understanding the contributions of the structural features of these molecules for receptor affinity and subtype selectivity, if any, to guide further desi...
Article
The ability of RuCl3/NaIO4 to selectively oxidize primary hydroxyl groups in the presence of secondary alcohols furnishing lactones is also demonstrated.
Article
Full-text available
Substituted gamma-butyrolactones represent an important group of structural fragments commonly found in natural products, receptor ligands, and drug molecules. Interest in preparing a library of substituted gamma-butyrolactones and finding that limited routes to beta-substituted lactones exist, led to the development of an efficient approach for th...
Article
Full-text available
Previous work identified the lactone ring as a useful scaffold for the design of muscarinic ligands and reported a lactone-based ligand with an IC50 of 340 nM. Using homologation as a lead modification approach, a new series of lactone-based compounds have been designed, synthesized, and screened in muscarinic binding assays. The approach provided...
Article
Full-text available
Previous structure-activity relationship studies involving a series of lactone-based muscarinic ligands identified a lead compound containing a diphenylmethylpiperazine moiety (4; IC50 = 340 nM). The purpose of the present work is to investigate 1,3-benzodioxoles, 4,4-diethyl substituted tetrahydrofurans, 5-substituted oxazolidinones and chromones...
Article
Full-text available
Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4'-Trihydroxystilbene [trans-resveratro...
Article
Full-text available
Facile synthetic routes to new silicon-containing ligands (1–4) for retinoic acid receptors (RARs) are reported. The design of these RAR ligands is based on a pharmacophoric model that divides the molecules into three regions (A, B, and C). The series of ligands is unique in region A due to their acyclic nature and the presence of alkyl-substituted...
Article
Trans-3,5,4'-trihydroxystilbene (trans-resveratrol, RES) exhibits very low bioavailability due to extensive conjugative metabolism. Whether RES metabolites exhibit pharmacologic activity is of great interest. The present study aimed at synthesis of monoconjugates of RES - the 3- and 4' monosulfates (R3S and R4'S), and the 3- and 4' monoglucuronides...
Article
Full-text available
Lead lactone-based ligands with modest affinity for muscarinic receptors were modified based on structure–activity relationship data in the literature to provide a new series of 5-substituted 4,5-dihydro-2(3H)-furanones. The modifications included the addition of various nitrogen-containing heterocycles attached to substituted and unsubstituted aro...
Article
Previous work in our laboratory investigated the ability of ammonium glycyrrhizinate (GLA) and two related compounds (carbenoxolone and glycyrrhetinic acid) to inhibit the DNA-binding properties HMGB1 in an in vitro screening system based on a quantitative capillary electrophoresis mobility shift assay (CEMSA). Our results demonstrated that GLA and...
Article
A wide-ranging and practical synthesis of structurally diverse, sterically hindered N-arylpiperazines from 2,2'-(4-nitrophenylsulfonylazanediyl) bis(ethane-2,1-diyl) bis(4-nitrobenzenesulfonate) and substituted anilines has been achieved using microwave irradiation in acetonitrile followed by deprotection with PhSH.
Article
Full-text available
According to the Bylaws of AACP, the Research and Graduate Affairs Committee shall provide assistance to the Association in developing its research, graduate education, and scholarship agenda. This assistance may include facilitating colleges and schools in formulating and advancing legislative and regulatory initiatives and nurturing collaborative...
Article
Furanones are important synthetic intermediates commonly found in natural products, receptor ligands, and drug molecules. Unacceptable yields of substituted furanones obtained using a previously reported Prins reaction led to the development of a modified approach. Readily prepared substituted allylic esters were reacted under Prins reaction condit...
Article
Attempts to prepare substituted chromones as novel retinoids revealed that some chromones were unstable under Wadsworth-Horner-Emmons reaction conditions. Hence, Wittig reactions were used to prepare chromone-based compounds as potential retinoids. Firstly, Wittig reagents prepared from 3-bromomethyl-chromen-4-one were reacted with olefinic-aldehyd...
Article
Full-text available
Utilizing molecular modeling techniques and structure-activity relationship data from the literature, a series of 2- and 3-substituted chromones and related heterocycles have been designed and synthesized as retinoic acid receptor ligands. The compounds were prepared using known coupling reactions and Wittig-Horner-Emmons reaction conditions. These...
Article
A wide-ranging, efficient and practical synthesis of structurally diverse, sterically hindered N-aryl piperazines from 2,2'-(4-nitrophenylsulfonylazanediyl) bis(ethane-2,1-diyl) bis(4-nitrobenzenesulfonate) and substituted anilines has been achieved using microwave irradiation in acetonitrile followed by deprotection with PhSH. N-aryl piperazines a...
Article
Wittig-Horner-Emmons (WHE) reaction conditions were used in conjunction with other reactions to prepare benzophenone-based retinoid candidates. The chromone nucleus was reacted with triethyl 3-methyl-phosphonocrotonate to afford benzophenones following a known rearrangement of a reaction intermediate. Confirmations of the structure of rearranged pr...
Article
The in vitro metabolic kinetics of letrozole were investigated by incubating letrozole (10-500 microM) in female or male rat liver microsomes to assess the effect of gender and to predict the in vivo biotransformation characteristics of letrozole in rats. The effects of tamoxifen (TAM) on the metabolic kinetics of letrozole were also examined by in...
Article
Anticonvulsant 4,5 dihydro-3,3-dialkyl-2(3H)-furanones act at sites on the GABAA receptor complex. Novel 5-substituted esters and homologous ester and amido derivatives of 4,5 dihydro-3,3-diethyl-2(3H)-furanone were synthesized and evaluated for anticonvulsant activity in rodents and for affinity to a site on the GABAA receptor complex ([3H]TBOB)....
Article
Anticonvulsant properties of compounds that enhance GABA-mediated inhibition through modulatory sites on the GABAA receptor [phenobarbital (PB), clonazepam (CZP), -ethyl--methyl--thiobutyrolactone (-EMTBL)] were compared with anticonvulsant effects of compounds believed to be antagonists at these modulatory sites (Ro 15- 1788 and a-isopropyl--methy...
Article
A series of ethers containing pyrrolidine and/or pyridine bioisosteres was synthesized and evaluated as nicotinic ligands. The dimethylaminoethoxypridines 6 and 7 inhibited the specific bind of (-)-[3H]Nicotine with Ki values of 300 nM and 450 nM, respectively. Compounds 8 and 9 were found to have Ki values of 3390 nM and 360 nM. These results sugg...
Article
A series of 5-substituted 4,5 dihydro-3,3-diethyl-2(3H)-furanones were prepared and evaluated as ligands for cholinergic receptors. 3,3-Diethyl-5-imidazolylmethyl-2(3H)-furanone (12), showed a three-fold selectivity for the M2 receptor subtype as compared to M1 or M3 receptors in preliminary studies. The effect of alkyl-substitution on the imidazol...
Article
Recent studies suggest that neuronal nicotinic acetylcholine receptors (nAChRs) may play a role in several CNS disorders and that subtype selective nicotinic ligands may be useful in the treatment of these disorders. Ethyl (3-quinuclidinyl)acetate (EQA) is a bulky, reverse-ester analog of ACh, that produces signs of cholinergic stimulation that may...
Article
Dihydro-2(3H)-furanones (gamma-butyrolactones) and dihydro-2(3H)-thiophenones (gamma-thiobutyrolactones) containing fluoroalkyl groups at positions C-3, C-4, and C-5 of the heterocyclic rings were prepared. The anticonvulsant/convulsant activities of the compounds were evaluated in mice. Brain concentrations of the compounds were determined and the...
Article
A series of 3-substituted quinuclidines were synthesized and evaluated as nicotinic ligands. Compound 2 inhibited the specific binding of [ 125I]-α-bungarotoxin and [ 3H]cytisine with IC 50 values of 2.26 μM and 22.7 μM, respectively. Compounds 1 and 2 produced contraction of the frog rectus abdominus muscle with ED 50 values of 10.7 μM and 13.2 μM...
Article
Anticonvulsant α-alkyl-substituted γ-butyrolactones (e.g. 1) are believed to act at sites on the GABAA receptor complex. Novel aminomethyl and amidomethyl derivatives of α-diethyl-γ-butyrolactone (1), 2 and 3, respectively, were synthesized and evaluated in radioligand binding assays ([35S]TBPS; IC50) and for anticonvulsant activity (ED50). The res...
Article
Tetrabenazine (TBZ) and dihydrotetrabenazine are well known inhibitors of the CNS vesicular monoamine transporter (VMAT), which is responsible for the packaging of monoamine neurotransmitters in presynaptic vesicles. Amino and amido derivatives of tetrabenazine were prepared as potential ligands for the vesicular monoamine transporter. Ultimately,...
Article
Binding characteristics of a novel radioiodinated tetrabenazine (TBZ) analog (iodovinyltetrabenazine; 125I-TBZ-Fraction I) were evaluated. In rat striatal homogenates, 125I-TBZ-I displayed a pharmacological profile consistent with specific binding to vesicular monoamine transport (VMAT) sites. In vitro autoradiographic studies using rat brain secti...
Article
Novel diamide dimercaptide (N2S2) ligands 4, 5, and 8 have been synthesized and evaluated as potential renal radiopharmaceuticals. The target compounds were prepared in modest overall yields of 22%, 19%, and 20%, respectively, using readily available starting materials. Following in situ deprotection, 99mTc complexes of high radiochemical purity we...
Article
A derivative of tetrabenazine (TBZ, 1) containing an iodovinyl group (I-TBZ, 3b) was prepared as a potential radiotracer for the vesicular monoamine transporter. The synthesis of 3a was achieved by ethynylation of TBZ. The ethynyl derivative 4, was converted to the corresponding vinylstannane 5. The vinylstannane intermediate was then treated with...
Article
A fluorinated derivative of an anticonvulsant γ-butyrolactone [α-(1,1-difluoroethyl)-α-methyl-γ-butyrolactone; γ-DFGBL] was synthesized as a probe for NMR spectroscopic observation of the drug in brain tissue. The fluorinated compound is an efficacious anticonvulsant in mice, and inhibits the specific binding of [35S]t-butylbicyclophosphorothionate...
Article
Anticonvulsant properties of compounds that enhance GABA-mediated inhibition through modulatory sites on the GABAA receptor [phenobarbital (PB), clonazepam (CZP), alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL)] were compared with anticonvulsant effects of compounds believed to be antagonists at these modulatory sites (Ro15-1788 and...
Article
A series of gamma-butyrolactones and gamma-thiobutyrolactones possessing a variety of alkyl groups and alkyl-substitution patterns was prepared and evaluated for anticonvulsant and convulsant activity. Behavioral studies performed on these compounds suggest that maximal anticonvulsant activity (against maximal electroshock and pentylenetetrazol) re...
Article
A number of investigators have shown that gamma-butyrolactones bind to the picrotoxin site on the gamma-aminobutyric acid (GABA) receptor. We examined the effects of three fluorinated gamma-butyrolactone derivatives on GABA currents and synaptic currents in cultured hippocampal neurons. alpha-(2,2,2-trifluoroethyl)-alpha-methyl-gamma-butyrolactone...
Article
Starting with easily prepared olefinic esters, efficient and versatile routes for the synthesis of γ-butyrolactones possessing a variety of alkyl-groups and alkyl-substitution patterns are reported.
Article
The actions of convulsant and sedative barbiturates on responses to γ-aminobutyric acid (GABA) application and on inhibitory postsynaptic currents were compared using voltage-clamp techniques in cultured rat hippocampal neurons. The convulsant barbiturates, 5-ethyl-5-(3-methylbut-2-enyl) barbituric acid (3M2B), and (+)-5-ethyl-5-(1,3-dimethylbutyl)...

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Projects (2)
Project
We hypothesize that the 5-HT7 receptor is involved the inflammatory process and that attenuating the actions of serotonin at these receptors will prove useful in the treatment of inflammatory disorders.