186593-31-7Relevant academic research and scientific papers
Development of 99mTc radiolabeled A85380 derivatives targeting cerebral nicotinic acetylcholine receptor: Novel radiopharmaceutical ligand 99mTc-A-YN-IDA-C4
Mori, Daisuke,Kimura, Hiroyuki,Kawashima, Hidekazu,Yagi, Yusuke,Arimitsu, Kenji,Ono, Masahiro,Saji, Hideo
, p. 4200 - 4210 (2019/08/12)
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (99mTc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent α4β2-nAChR agonist, we prepared A85380 derivatives labeled with 99mTc using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a 99mTc analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at α4β2-nAChR in both the docking simulation (?19.3 kcal/mol) and binding assay (Ki = 0.4 ± 0.04 nM). Further, 99mTc-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that 99mTc-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR in vitro and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.
Nickel-mediated radioiodination of aryl and heteroaryl bromides: Rapid synthesis of tracers for SPECT imaging
Cant, Alastair A.,Champion, Sue,Bhalla, Rajiv,Pimlott, Sally L.,Sutherland, Andrew
supporting information, p. 7829 - 7832 (2013/08/23)
Rapid and efficient radioiodination of aryl and heteroaryl bromides has been achieved using a nickel(0)-mediated halogen-exchange reaction. This transformation gives direct access to [123I]- and [ 125I]-imaging agents for single photon emission computed tomography (SPECT), such as 5-[123I]-A85380 (see scheme, Boc=tert- butyloxycarbonyl, cod=1,5-cyclooctadiene, TFA=trifluoroacetic acid). Copyright
PHENYL-SUBSTITUTED NICOTINIC LIGANDS, AND METHODS OF USE THEREOF
-
Page/Page column 40; 43, (2013/05/23)
Disclosed are compounds and methods of using them to treat a disorder selected from the group consisting of addiction, pain, obesity, schizophrenia, epilepsy, mania and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder (ADHD), Parkinson's disease, Huntington's disease, Tourette's syndrome, amyotrophic lateral sclerosis, inflammation, stroke, spinal cord injury, dyskinesias, obsessive compulsive disorder, chemical substance abuse, alcoholism, memory deficit, pseudodementia, Ganser's syndrome, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome, tobacco abuse, post-traumatic syndrome, social phobia, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, autism, mutism, trichotillomania, hypothermia, and disorders of sleep.
Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands
Yenugonda, Venkata M.,Xiao, Yingxian,Levin, Edward D.,Rezvani, Amir H.,Tran, Thao,Al-Muhtasib, Nour,Sahibzada, Niaz,Xie, Teresa,Wells, Corinne,Slade, Susan,Johnson, Joshua E.,Dakshanamurthy, Sivanesan,Kong, Hye-Sik,Tomita, York,Liu, Yong,Paige, Mikell,Kellar, Kenneth J.,Brown, Milton L.
, p. 8404 - 8421 (2013/12/04)
Developing novel and selective compounds that desensitize α4β2 nicotinic acetylcholine receptors (nAChRs) could provide new effective treatments for nicotine addiction, as well as other disorders. Here we report a new class of nAChR ligands that display high selectivity and picomolar binding affinity for α4β2 nicotinic receptors. The novel compounds have Ki values in the range of 0.031-0.26 nM and properties that should make them good candidates as drugs acting in the CNS. The selected lead compound 1 (VMY-2-95) binds with high affinity and potently desensitizes α4β2 nAChRs. At a dose of 3 mg/kg, compound 1 significantly reduced rat nicotine self-administration. The overall results support further characterizations of compound 1 and its analogues in preclinical models of nicotine addiction and perhaps other disorders involving nAChRs.
NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF
-
Paragraph 1290; 1291, (2013/07/25)
The invention relates to pyridinyl nicotinic acetylcholine receptor ligands, compositions comprising an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand and methods to treat or prevent a condition, such as depression and nicotine dependence, comprising administering to an animal in need thereof an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand.
SILENT DESENSITIZERS OF NEURONAL NACHR AND METHODS OF USE THEREOF
-
Page/Page column 41-42; Figure 1a, (2009/12/27)
One aspect of the present invention relates to heterocyclic compounds that are ligands for nicotinic acetylcholine receptors. A second aspect of the invention relates to the use of a compound of the invention for modulation of a mammalian nicotinic acetylcholine receptor.
Discovery of trans-3,4′-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation
Li, Qun,Li, Tongmei,Zhu, Gui-Dong,Gong, Jianchun,Claibone, Akiyo,Dalton, Chris,Luo, Yan,Johnson, Eric F.,Shi, Yan,Liu, Xuesong,Klinghofer, Vered,Bauch, Joy L.,Marsh, Kennan C.,Bouska, Jennifer J.,Arries, Shannon,De Jong, Ron,Oltersdorf, Tilman,Stoll, Vincent S.,Jakob, Clarissa G.,Rosenberg, Saul H.,Giranda, Vincent L.
, p. 1679 - 1685 (2007/10/03)
A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4′-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC50 values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined.
LIGANDS FOR NICOTINIC ACETYLCHOLINE RECEPTORS, AND METHODS OF MAKING AND USING THEM
-
Page 91-92, (2010/02/10)
One aspect of the present invention relates to heterocyclic compounds that are ligands for nicotinic acetylcholine receptors. A second aspect of the invention relates to the use of a compound of the invention for modulation of a mammalian nicotinic acetylcholine receptor. The present invention also relates to the use of a compound of the invention for treating a mammal suffering from Alzheimer's disease, Parkinson's disease, dyskinesias, Tourette's syndrome, schizophrenia, attention deficit disorder, anxiety, pain, depression, obsessive compulsive disorder, chemical substance abuse, alcoholism, memory deficit, pseudodementia, Ganser's syndrome, migraine pain, bulimia, obesity, premenstrual syndrome or late luteal phase syndrome, tobacco abuse, post-traumatic syndrome, social phobia, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism or trichtillomania.
Synthesis of 3-[(2S)-azetidin-2-ylmethoxy]-5-[11C]-methylpyridine, an analogue of A-85380, via a Stille coupling
Karimi, Farhad,Lngstrm, Bengt
, p. 423 - 434 (2007/10/03)
3-[(2S)-azetidin-2-ylmethoxy]-5-[11C]-methylpyridine (5d), which might be a novel ligand for nicotinic receptors, was synthesized via coupling [11C]iodomethane with tert-butyl (2S)-2-({[5-(trimethylstannyl)pyridin-3-yl]oxy}methyl) azetidine-1-carboxylate (4) at 80°C for 5 min with tri-o-tolylphosphine-bound, unsaturated palladium(O), followed by deprotection using trifluoroacetic acid (TFA). The previous problem (solid-phase extraction before injection on semi-preparative LC) with automation of Stille coupling reactions has been overcome. In a typical experiment, 0.46 GBq of 5d was obtained from 5.2GBq of [11C]iodomethane. The decay-corrected radiochemical yield was 39% (based on the quantity [11C]iodomethane trapped). The synthesis time was 43 min from end of radionuclide production. During a production condition using 36 μAh of proton beam irradiation, a specific radioactivity of 50 GBq/ μmol of the final product was obtained in biological buffer. Copyright
