Date of Award
Doctor of Philosophy
James M Cook
Alexander E Arnold, Alan W Schwabacher, Arsenio A Pacheco, Xiaohua Peng
A series of α2/3-subtype selective GABAA receptor agonist imidazodiazepines (IBZs) were synthesized and investigated. The lead compound (KRM-II-81) exhibited anxiolytic, antinociceptive and anticonvulsant effects, displayed promising α2/3 GABAergic subtype selectivity in HEK cells and noteworthy anxiolytic activity and no sedation nor ataxia using a rotarod assay in mice (80mg/Kg) or rats (300 mg/Kg).Based on the "privileged imidazodiazepine (IMZD) structures" derived from the unified pharmacophore model of Milwaukee, the design, synthesis and biological activities of more than 30 novel 2’ Cl achiral GABAAR α2/α3 subtype selective imidazodiazepines (IMDZs) related to KRM-II-81 achiral ligand Hz-166 are described. Several compounds from the α2/3 subtype selective group are anxiolytic, antidepressant, and are targeted toward the treatment of major pain, epilepsy disorders. In regard to the design of new 2’Choloro benzodiazepine analog, an improved large-scale synthesis of (2-amino-5-bromophenyl) (2-chlorophenyl) (4)was performed which is very expensive in market (1800 USD/ 500g). A novel synthetic route with minimal costfor large quantity production of the (4) was described here. After several attempt and optimization, the yield of 2 amino 5 bromo 2’Cl benzophenone was increased from 35-44%. No column chromatography was needed to purify the large-scale product. This new developed route to synthesize of (2-amino-5-bromophenyl) (2-chlorophenyl can be applied to synthesize another benzophenone with different substituents. FR-II-60 and more than 30 analogs were designed, synthesized, and evaluated where (4) was used as a starting material. The goal of this research is to design new analogs with improved metabolic stability that also retain the desired biological properties with little or no side effects for the treatment of CNS disorders, pain. The α2/3 selective achiral oxazole, FR-II-60 looks very good in rodent models for the treatment of epilepsy and pain. It exhibited anti-depressant and anxiolytic activities in mice. It shows sightly sedation using a rotarod assay in mice (40, 80mg/Kg) due to the presence of halogen (Cl) at 2’ position in its structure. No cytotoxicity observed in HEK293 cell in lower concentration (up to 300 uM). Behavioral observations in female rhesus monkeys after the administration of FR-II-60 (3mg/kg, iv) did not show any deep sedation. Further study of this compound is presently taking place. According to the data and ongoing research FR-II-60 looks very promising ligand to treat conditions such as chronic pain and epilepsy. After evaluation of a series of novel IMDZs that were α5 subtype selective for the treatment of asthma, one compound MIDD0301 (originally named GL-II-93) was found to be orally active and as an inhalant in rodent asthma models. Ligand MYM-FR-II-88 and FR-III-45 was as active as GL-II-93 in the airway smooth muscle (ASM) relaxation assay. FR-III-45 does not induce any immunotoxicity in animal models as well as no sedation nor ataxia using a rotarod assay in mice up to dose 40 mg/Kg. This research is still ongoing and several ligands, especially the α5 subtype selective acid, described herein have been shown to relax precontracted human and guinea pig airway smooth muscle and could deliver a novel treatment for asthma patients. The medulloblastoma is known as a Pediatric brain cancer, It’s subtype, subgroup 3 also has a high expression of the. GABRA5. The α 5 selective ligand QH-II-066 and KRM-II-08 positive allosteric modulators showed very high potency in cell viability by decreasing the expression of HOXA5 which is a homeobox transcription factor that controls p53 expression. To understand the role of α5-GABAAR in group 3 cell viability, 763 primary medulloblastoma patient tumor has been studied. Two ligands FR-I-44 and FR-I-43 have also been screened in a particular cell line D283 and did not show appreciable potency compared to KRM-II-080. Although these ligands did not show any cytotoxicity in HEK293 cell, it might show some potency in other cancer cell lines- an area of research that is currently ongoing.
Rashid, Farjana, "Design and Synthesis of Achiral and Chiral Benzodiazepines and Imidazodiazepines to Modulate the Activity of Gabaa Receptors for the Treatment of Cancer, CNS Disorders and Pain" (2021). Theses and Dissertations. 2827.
Available for download on Friday, September 01, 2023