Potent Triple Reuptake Inhibitor Research Articles

Novel Potent Dopamine-Norepinephrine and Triple Reuptake Uptake Inhibitors Based on Asymmetric Pyran Template and Their Molecular Interactions with Monoamine Transporters.

We have carried out a structural exploration of (2S,4R,5R)-2-(bis(4-fluorophenyl)methyl)-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-473) to investigate the influence of various functional groups on its aromatic ring, the introduction of heterocyclic aromatic rings, and the alteration of the stereochemistry of functional group on the pyran ring. The novel compounds were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting monoamine neurotransmitter uptake. Our studies identified some of the most potent dopamine-norepinephrine reuptake inhibitors known to-date like D-528 and D-529. The studies also led to development of potent triple reuptake inhibitors such as compounds D-544 and D-595. A significant influence from the alteration of the stereochemistry of the hydroxyl group on the pyran ring of D-473 on transporters affinities was observed indicating stereospecific preference for interaction. The inhibitory profiles and structure-activity relationship of lead compounds were further corroborated by molecular docking studies at the primary binding sites of monoamine transporters. The nature of interactions found computationally correlated well with their affinities for the transporters.

Toxicity effects of a novel potent triple reuptake inhibitor, LPM570065, on the fertility and early embryonic development in Sprague-Dawley rats

Selective serotonin reuptake inhibitors (SSRIs) have developed as novel antidepressants and have been determined to possess higher efficacy and less adverse effects compared to other antidepressants. Our previous studies have showed that LPM570065, a new potent TRI, is relatively nontoxic in acute, subchronic toxicity and genotoxicity evaluations. In the current study, toxicity of LPM570065 was further evaluated on the fertility and early embryonic development in Sprague-Dawley rats. A total of 264 rats were treated with various concentrations of LPM570065 (30 mg/kg, 100 mg/kg, and 300 mg/kg) or used as control. Females rats were treated for two consecutive weeks, followed by mating via cohabitation up to the 7th gestation day (GD). The male rats were treated for four consecutive weeks, which were followed by first mating with treated female rats. Then, all males were treated up to the 9th week and followed by second mating with non-treated female rats, and were sacrificed. All surviving pregnant females were euthanized on GD 15. We evaluated the following parameters, namely, mortality, toxicity symptoms, body weight, amount of food consumed, sexual cycle, mating behavior, pregnancy, sperm production, gross necropsy, and weight of organs. Excessive salivation was observed post treatment in nearly all females and males in the 100 and 300 mg/kg LPM570065 treatment groups. Body weight gain was decreased in gravid rats treated with 300 mg/kg LPM570065 during GD 0–6 (P < 0.05). The application of 300 mg/kg of LPM57006 to male rats induced a decrease in implantation sites and lower fertility rates (P < 0.05). However, sperm concentration and count were higher in the LPM570065-treated groups (30 mg/kg, 100 mg/kg, and 300 mg/kg) compared to the controls. Moreover, duration of mating significantly decreased to 37.5% after nine weeks of LPM570065 treatment at a concentration of 300 mg/kg (P < 0.05). In conclusion, the no observable adverse effect level (NOAEL) was established at 100 mg/kg and 300 mg/kg for female and male rats, respectively. The NOAEL for fertility and early embryonic development was established at 300 mg/kg and 100 mg/kg for female and male rats, respectively.

Acute, subchronic oral toxicity, and genotoxicity evaluations of LPM570065, a new potent triple reuptake inhibitor

In the current study, to support the safety of LPM570065 as a new potent triple reuptake inhibitors (TRIs), LPM570065 was investigated through a single- and 13-week repeated-dose oral toxicity evaluation and mutagenicity assays. In an acute toxicity evaluation, Sprague-Dawley (SD) rats were single administration at dose of 500, 1000 and 2000 mg/kg. The results suggested that two (2/20) and seven (7/20) animals were died in the 1000 and 2000 mg/kg group, respectively. In contrast, there were no treatment-related effects at a dose of 500 mg/kg. In a 13-week toxicity evaluation, SD rats were given 30, 100, or 300 mg/kg LPM570065 for 13 successive weeks and then allowed a 4-week recovery period. Impermanent salivation was found at each of the doses, and an impermanent minor body weight decrease was noted in the 300 mg/kg males (P < 0.05). Notably, serum prolactin levels were lowered by 43.25% and 78.65% in the male rats in 100 and 300 mg/kg groups, respectively (P < 0.05). Further, the serum testosterone was elevated by 37% in the 30 and 100 mg/kg males. In conclusion, the maximum tolerated dose (MTD) was 500 mg/kg and the lethal dose was 1000 mg/kg in SD rats after a single administration of LPM570065. In 13-week repeated-dose oral toxicity, the no-observed-adverse-effect level (NOAEL) of LPM570065 was greater than 300 mg/kg for rats. Moreover, LPM570065 was not mutagenic or clastogenic. According to this result it can be concluded that the MTD of LMP570065 is approximately up to 3000 mg/person/day in clinic, and the effects of LMP570065 on sexual function also should be considered.

Centrally Acting Agents for Obesity: Past, Present, and Future.

For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long term. This review of central nervous system (CNS) acting anti-obesity drugs evaluates current therapies such as phentermine/topiramate, which act through multiple neurotransmitter pathways to reduce appetite. In the synergistic mechanism of bupropion/naltrexone, naltrexone blocks the feed-back inhibitory circuit of bupropion to give greater weight loss. Lorcaserin, a selective agonist of a serotonin receptor that regulates food intake, and the glucagon-like-peptide-1 (GLP-1) receptor agonist liraglutide are reviewed. Future drugs include tesofensine, a potent triple reuptake inhibitor in Phase III trials for obesity, and semaglutide, an oral GLP-1 analog approved for diabetes and currently in trials for obesity. Another potential new pharmacotherapy, setmelanotide, is a melanocortin-4 receptor agonist, which is still in an early stage of development. As our understanding of the communication between the CNS, gut, adipose tissue, and other organs evolves, it is anticipated that obesity drug development will move toward new centrally acting combinations and then to drugs acting on peripheral target tissues.

Enantioselective synthesis of BMS-911278: a triple reuptake inhibitor

BMS-911278 was identified as a potent triple reuptake inhibitor potentially useful for the treatment of depression. The original racemic synthesis suffered from tedious and low recovery resolution and HPLC separation, as well as low-yielding hazardous N-demethylation at the API step. To support further preclinical studies, a scalable enantioselective synthesis was developed. Herein, we report an efficient asymmetric synthesis of BMS-911278 featuring two key steps: an enantioselective Miyaura reaction and an intramolecular regioselective cyclization.

Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors

We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.

Preclinical pharmacology of TP1, a novel potent triple reuptake inhibitor with antidepressant properties

Triple reuptake inhibitors (TRIs) that block the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) are being developed as a new class of antidepressant that may have better efficacy and fewer side effects compared with traditional antidepressants. The purpose of this study was to characterize a new chemical entity, 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl] phenyl 4-methoxybenzoate hydrochloride (TP1). TP1 was designed as a prodrug of desvenlafaxine. Competitive radioligand binding assays were performed using cells expressing the human dopamine (DA) transporter (hDAT), the human serotonin (5-HT) transporter (hSERT), and the human norepinephrine (NE) transporter (hNET) with K(i) values for TP1 of 190 nM, 2076 nM, and 1023 nM, respectively. Uptake assays were performed with IC(50) values for TP1 of 712 nM, 521 nM, and 628 nM, respectively. TP1 (0.06 mmol/kg, orally) rapidly penetrated rat brain and hypothalamus, translated into desvenlafaxine within 1 h, and demonstrated higher bioavailability and better pharmacokinetic properties than desvenlafaxine succinate (DVS). TP1 (0.06 mmol/kg, orally) significantly increased extracellular levels of DA, NE, and 5-HT compared with baseline in the rat hypothalamus by microdialysis assay. In dose-response assays, oral administration of TP1 reduced the time of immobility in a dose-dependent manner during tail suspension test and forced swimming test (FST). This antidepressant-like effect manifests in the absence of significant increases in motor activity even at doses of up to 32 mg/kg. The ability of TP1 to inhibit the reuptake of three biogenic amines closely linked to the etiology of depression may result in a therapeutic profile different from antidepressants that inhibit the reuptake of serotonin and/or NE.

Chiral Synthesis of an α-Tetrasubstituted Proline Derivative

Triple reuptake inhibitors (TRIs) have been identified as possible alternative treatments for central nervous system disorders. A practical synthesis was investigated to access a potent TRI, (4-amino-3-chloro-phenyl)-((S)-2-isobutyl-pyrrlidin-2-yl)-methanone (1), starting from alkylation of D-proline. Improved routes to key intermediates are discussed and demonstrated by an expedient multigram production of 1.

Synthesis and Pharmacological Characterization of Bicyclic Triple Reuptake Inhibitor 3-Aryl Octahydrocyclopenta[c]pyrrole Analogues

The present work expands the chemical space known to offer potent inhibition of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) and discloses novel bicyclic octahydrocyclopenta[c]pyrrole and octahydro-1H-isoindole scaffolds as potent triple reuptake inhibitors (TRIs) for the potential treatment of depression. Optimized compounds 22a (SERT, NET, DAT, IC(50) = 20, 109, 430 nM), 23a (SERT, NET, DAT, IC(50) = 29, 85, 168 nM), and 26a (SERT, NET, DAT, IC(50) = 53, 150, 140 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 10 and 30 mpk PO, and were not generally motor stimulants at doses ranging from 1 to 30 mpk PO. Moderate in vitro cytochrome P450 (CYP) and potassium ion channel Kv11.1 (hERG) inhibition were uncovered as potential liabilities for the chemical series.

1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane: Further insights into a class of triple re-uptake inhibitors

Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the ‘titration’ of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.