Lalit K. Golani

Northeastern University | NEU

Background: Benzodiazepines bind to γ-aminobutyric acid type A (GABAA) receptor subtypes identified by different α subunits (i.e., α1GABAA, α2GABAA, α3GABAA, and α5GABAA). Sedative-motor effects of benzodiazepines are thought to involve α1GABAA and α3GABAA subtypes. Aims: We evaluated observable measures of sedative-motor effects and species-typ...

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved...

Chapter Two discusses how α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors represent a novel and potentially-improved approach to dampening uncontrolled excitatory neural transmission in neurology and psychiatry.

Introduction: Deficiencies in standard of care antidepressants are driving novel drug discovery. A new age of antidepressant medications has emerged with the introduction of rapid-acting antidepressants with efficacy in treatment-resistant patients. Areas covered: The newly approved medicines and those in clinical development for major depressiv...

A series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole known as KRM-II-81) is currently awaiting advancement into the clinic. A deuterated st...

In order to provide back-up compounds to support the development of the GABAA receptor (GABAAR) potentiator, KRM-II-81, three novel analogs were designed: replacement of the pyridinyl with Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPP-III-34 and KPP-III-51), or substitutio...

Prenatal alcohol exposure (PAE) has shown to induce symptomatology associated with attention deficit hyperactivity disorder (ADHD) by altering neurodevelopmental trajectories. Phosphodiesterase-1 (PDE1) are expressed centrally and have been used in various experimental brain conditions. We investigated the role of vinpocetine a PDE1 inhibitor, on b...

Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABAA receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standar...

The imidazodiazepine, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a new α2/3-selective GABAkine (GABAA receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half-lif...

The pharmacological actions exerted by benzodiazepines are dependent on the discrete α protein subunits of the γ-aminobutyric acid type A receptor (GABAA R). Recent developments via a cryo-EM structure of the α1β3γ2L GABAA R ion channel provide crucial insights into ligand efficacy and binding affinity at this subtype. We investigated the molecular...

GABAA receptors have long been known to be important modulators of pain but the development of pain-modifying medicines based upon this mechanism has been hampered in large part due to the sedative liabilities associated with potentiation of GABAA receptors. A recently discovered compound, 5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4...

Positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependenc...

In order to develop improved anxiolytic drugs, 8-substituted analogs of triazolam were synthesized in an effort to discover compounds with selectivity for α2/α3 subunit-containing GABAA subtypes. Two compounds in this series, XLi-JY-DMH (6-(2-chlorophenyl)-8-ethynyl-1-methyl-4H-benzo [f][1,2,4]triazolo[4,3-a][1,4]diazepine) and SH-TRI-108 [(E)-8-et...

This article provides the biologist, chemist, and clinician with an overview into currently existing epilepsy medicines, an appreciation of those currently in development, and a glimpse at future possibilities. The discovery and development of antiepileptic drugs with improved efficacy and side‐effect dimensions are urgently needed. We discuss vari...

Background Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Maternal consumption of alcohol is known to produce deleterious effects in the progeny, generating ADHD related phenotypes. Phosphodiesterase-3 (PDE3) has been shown to provide benefits in various brain conditions. Obj...

Benzodiazepines bind to and act on α1-3 and α5-containing GABAA receptors. Previous studies suggest that different GABAA receptor α-subtypes mediate the various behavioral effects of benzodiazepines, which raises the possibility of combining benzodiazepines with subtype-selective GABAA receptor antagonists to improve the therapeutic profiles of ben...

We dedicate this work to Professor Jan Bergman for his outstanding contributions to heterocyclic and organic chemistry as a whole Abstract Antinociceptive ligand HZ-166 is a GABA A 2/3 receptor subtype-selective potentiator. It has been shown to exhibit anxiolytic-like effects in rodent and rhesus monkeys, as well as reduced sedative/ataxic liabi...

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase‐10A (PDE10A) has been shown to provide benefits in various brain conditions. We investigated the role of papaverine, a selective PDE10A inhibitor on core phenotypes in prenatal alcohol exposure (PAE) model of ADH...

The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of α2/3-containing GABAA receptors (5-(8-ethynyl-6-(pyridin...

Opiate analgesics are one of the treatment options for severe chronic pain, including late-stage cancer, chronic back pain and other disorders. The recent resurgence in opioid overdose has highlighted the serious need for alternative medicines for pain management. While a role for potentiators of α2/3-containing GABAA receptors in the modulation of...

Conventional antidepressants typically require weeks of daily dosing to achieve full antidepressant response in antidepressant responders. A newly evolving group of compounds can engender more rapid response times in depressed patients. These drugs include the newly approved antidepressant (S)-ketamine (esketamine, Spravato). A seminal study by Fur...

Tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine benzoyl compounds based on 2 were isosterically modified at the 4-carbon bridge by replacing the vicinal (C11) carbon by heteroatoms N (4), O (5) or S (6), or with an N-substituted formyl (7), trifluoroacetyl (8) or acetyl (9). Replacement with sulfur (6) afforded the most potent KB tumor cell i...

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports on cestode and trematode infections with poor PZQ cure-ra...

The imidizodiazepine, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81), is selective for α2/3-containing GABAA receptors. KRM-II-81 dampens seizure activity in rodent models with enhanced efficacy and reduced motor-impairment compared to diazepam. In the present study, KRM-II-81 was studied in assa...

INTRODUCTION Epilepsy patients continue to suffer from the lack of efficacious medications. Recent attention has been directed toward the potential advantages of developing positive allosteric modulators of alpha-2/3-containing γ-aminobutyric acid type A (GABAA) receptors as antiepileptic drugs. A proof of principle has been reported with one such...

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports of cestode and trematode infections with poor PZQ cure-ra...

The need for improved antiepileptics is clearly mandated despite the existence of multiple existing medicines from different chemical and mechanistic classes. Standard of care agents do not fully control epilepsies and have a variety of side-effect and safety issues. Patients typically take multiple antiepileptic drugs and yet many continue to have...

Background Previous studies have investigated α1GABAA and α5GABAA receptor mechanisms in the behavioral effects of ethanol (EtOH) in monkeys. However, genetic studies in humans and preclinical studies with mutant mice suggest a role for α2GABAA and/or α3GABAA receptors in the effects of EtOH. The development of novel positive allosteric modulators...

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABA A receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABA A receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABA A receptor...

This study examined effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 in an assay of pain-related behavioral depression. Adult, male Sprague-Dawley rats responded for electrical brain stimulation in a frequency-rate intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of 1.8% lactic a...

Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, la...

Enhancement of GABAA receptor inhibition has long been used in the treatment of anxiety beginning with meprobamate, diazepam, chlordiazepoxide, and alprazolam in present times. Positive allosteric modulation of GABAA receptors has thus proven its place in medical practice. Subsequent work focused on the design of compounds with reduced sedative lia...

Fatigue is common in a host of neurological and psychiatric disorders including depression and often continues unabated even after primary symptoms of disease are treated. Its high estimated prevalence combined with the lack of effective medicines has engaged the preclinical research community to search for fatigue models. The present review briefl...

An improved synthesis of the anxiolytic, anticonvulsant, and antinociceptive compounds: Hz-166, and its bioisosteres 1,2,4-oxadiazole (MP-III-080) and 1,3-oxazole (KRM-II-81) were synthesized in higher yields and with more facile purification methods (crystallization, etc.) in multigram quantities without column chromatography. In the synthesis of...

Data from transgenic animals and novel pharmacological agents has realigned scientific scrutiny on the therapeutic potential of positive allosteric modulators (PAMs) of α2/3-containing GABAA receptors. Evidence for analgesic, anticonvulsant, and anxiolytic activity of α2/3-selective PAMs has been presented along with the clinical potential for a mi...

Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) α and β or the proton-coupled folate transporter. Results show inc...

Reduced folates are essential cofactors for the biosynthesis of purines and pyrimidines. Since humans do not synthesize folate, it is necessary to obtain these cofactors from dietary sources. In mammals, three specialized systems exist that mediate membrane transport of folates and antifolates across biological membranes. These include the reduced...

Structure-activity relationships for cellular uptake and inhibition of cell proliferation were studied for 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates in which the terminal l-glutamate of the parent structure (7) was replaced by natural or unnatural amino acids. Compounds 7 and 10-13 were selectively inhibitory toward...

We have been extensively involve in the elaboration of substitute pyrrolo[2,3-]pyrimiines to obtain potential targete agents without reuce folate carrier (RFC) activity. Lack of selectivity for RFC is a major cause of significant toxicity in the clinic associate with antifolate anticancer agents. These efforts have le to the iscovery of several ser...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Reduced folates are essential cofactors for biosynthesis of purines and pyrimidines. Since humans do not synthesize folate, it is necessary to obtain these cofactors from dietary sources. In mammals, three specialized systems exist that mediate membrane transport of fola...

Spiro 1,2,4-trioxane are synthetic derivative of artemisinin (1,2,4-trioxane is supposed to be a pharmacophore of artemisinin) which is a well known antimalarial drug from leaves of Artemisia annua found in China. Spiro 1,2,4-trioxane substituted with admantane and its 4 different derivatives were synthesized using well standardized method. These c...

A simple and sensitive spectroscopic method in ultraviolet region was developed and validated for the estimation of Furazolidone in pure and pharmaceutical dosage forms. The method is based on Furazolidone, showing absorbance at 259 nm for zero order derivative spectroscopy respectively in acetonitrile and distilled water. This method obey's Beers...

Mangiferin is the active constituent obtained from the dried parts such as leaves and barks of the Mango tree (Mangifera indica L.) which belongs to the family Anacardiaceae. Analytical method is developed and validated for the determination of Mangiferin in Mangifera indica by reversed-phase HPLC method. The HPLC method is described for determinat...

3-(1-Phenyl-vinyl)-1, 2, 5-trioxa-spiro undecane is synthetic derivative of Artemisinin. Artemisinin is a well known antimalarial drug from leaves of Artemisia annua find in china. Five different derivatives of 3-(1-Phenyl-vinyl)-1, 2, 5-trioxa-spiro undecane were synthesized using well standardized method. These compounds were purified by simple c...

Malaria is a major parasitic disease, affecting over 100 countries of the tropical and subtropical regions of the world.1 Around 300-500 million clinical cases of malaria are reported every year, of which more than a million die of severe and complicated cases of malaria.2 It is fatal for children below the age of 5 years. Every 40 seconds a child...