Isoquinolone derivatives as lysophosphatidic acid receptor 5 (LPA5) antagonists: Investigation of structure-activity relationships, ADME properties and analgesic effects.

Blockade of lysophosphatidic acid receptor 5 (LPA5) by a recently reported antagonist AS2717638 (2) attenuated inflammatory and neuropathic pains, although it showed moderate in vivo efficacy and its structure-activity relationships and the ADME properties are little studied. We therefore designed and synthesized a series of isoquinolone derivatives and evaluated their potency in LPA5 calcium mobilization and cAMP assays. Our results show that substituted phenyl groups or bicyclic aromatic rings such as benzothiophenes or benzofurans are tolerated at the 2-position, 4-substituted piperidines are favored at the 4-position, and methoxy groups at the 6- and 7-positions are essential for activity. Compounds 65 and 66 showed comparable in vitro potency, excellent selectivity against LPA1-LPA4 and >50 other GPCRs, moderate metabolic stability, and high aqueous solubility and brain permeability. Both 65 and 66 significantly attenuated nociceptive hypersensitivity at lower doses than 2 and had longer-lasting effects in an inflammatory pain model, and 66 also dose-dependently reduced mechanical allodynia in the chronic constriction injury model and opioid-induced hyperalgesia at doses that had no effect on the locomotion in rats. These results suggest that these isoquinolone derivatives as LPA5 antagonists are of promise as potential analgesics.

Neuropeptide B/W receptor 1 peptidomimetic agonists: Structure-activity relationships and plasma stability.

Neuropeptides B and W (NPB and NPW) are endogenous ligands of the Neuropeptide B/W Receptor 1 (NPBWR1) which has been implicated in a wide range of functions including regulation of pain and energy homeostasis. There is currently little information on the structure-activity relationships (SAR) of these two neuropeptides. In a quest to develop stable and potent NPBWR1 peptidomimetic agonists, we performed systematic SAR by truncation, Alanine/Glycine and d-amino acid scans, and replacement with unnatural amino acids. Evaluation in the NPBWR1 calcium assay revealed that the C-terminal GRAAGLL and N-terminal WYK regions constitute the two-epitope pharmacophore for NPBWR1 agonism. Replacement of the N-terminal Trp with its desaminoTrp residue resulted in compound 30 which exhibited nanomolar potency comparable to the endogenous NPB at NPBWR1 (Calcium assay: EC50 = 8 nM vs. 13 nM, cAMP assay: 2.7 nM vs 3.5 nM) and enhanced metabolic stability against rat plasma (39.1 min vs. 11.9 min).

Oral administration of TiO2 nanoparticles during early life impacts cardiac and neurobehavioral performance and metabolite profile in an age- and sex-related manner.

BACKGROUND: Nanoparticles (NPs) are increasingly incorporated in everyday products. To investigate the effects of early life exposure to orally ingested TiO2 NP, male and female Sprague-Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight TiO2 NP (diameter: 21 ± 5 nm) or vehicle control (water) by gavage at three different pre-weaning ages: postnatal day (PND) 2-5, PND 7-10, or PND 17-20. Cardiac assessment and basic neurobehavioral tests (locomotor activity, rotarod, and acoustic startle) were conducted on PND 20. Pups were sacrificed at PND 21. Select tissues were collected, weighed, processed for neurotransmitter and metabolomics analyses. RESULTS: Heart rate was found to be significantly decreased in female pups when dosed between PND 7-10 and PND 17-20. Females dosed between PND 2-5 showed decrease acoustic startle response and when dosed between PND 7-10 showed decreased performance in the rotarod test and increased locomotor activity. Male pups dosed between PND 17-20 showed decreased locomotor activity. The concentrations of neurotransmitters and related metabolites in brain tissue and the metabolomic profile of plasma were impacted by TiO2 NP administration for all dose groups. Metabolomic pathways perturbed by TiO2 NP administration included pathways involved in amino acid and lipid metabolism. CONCLUSION: Oral administration of TiO2 NP to rat pups impacted basic cardiac and neurobehavioral performance, neurotransmitters and related metabolites concentrations in brain tissue, and the biochemical profiles of plasma. The findings suggested that female pups were more likely to experience adverse outcome following early life exposure to oral TiO2 NP than male pups. Collectively the data from this exploratory study suggest oral administration of TiO2 NP cause adverse biological effects in an age- and sex-related manner, emphasizing the need to understand the short- and long-term effects of early life exposure to TiO2 NP.

Intravenous administration of three multiwalled carbon nanotubes to female rats and their effect on urinary biochemical profile.

This study was conducted to investigate the influence of outer diameter (OD) and length (L) of multiwalled carbon nanotubes (MWCNTs) on biodistribution and the perturbation of endogenous metabolite profiles. Three different-sized carboxylated MWCNTs (NIEHS-12-2: L 0.5-2 µm, OD 10-20 nm, NIEHS-13-2: L 0.5-2 µm, OD 30-50 nm, and NIEHS-14-2: L 10-30 µm, OD 10-20 nm) in water were administered to female Sprague-Dawley rats as a single intravenous dose of 1 mg/kg MWCNTs. Biodistribution in liver, lung, spleen, and lymph nodes was evaluated in tissue sections at 1 and 7 days' post-dosing using enhanced darkfield microscopy and hyperspectral imaging. Nuclear magnetic resonance (NMR) analysis was used for biochemical profiling and pathway mapping of endogenous metabolites in urine collected at 24-h intervals prior to dosing, at Day 1 and Day 7. At Day 1 and Day 7, all three MWCNTs were observed in liver. NIEHS-12-2 was observed in spleen, whereas NIEHS-13-2 and NIEHS-14-2 were not. All three MWCNTs were observed in lymph nodes and lung at Day 7. The urinary biochemical profile showed the highest positive fold change (FC) at Day 7 for the metabolites acetate, alanine, and lactate, whereas 1-methylnicotinamide, 2-oxoglutarate, and hippurate had some of the lowest FCs for all three MWCNTs. This study demonstrates that the observed tissue location of MWCNTs is size dependent. Overlaps in the perturbation of endogenous metabolite profiles were found regardless of their size, and the biochemical responses were more profound at Day 7 compared with Day 1, indicating a delayed biological response to MWCNTs.

Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core.

Activation of the neuropeptide S receptor (NPSR) system has been shown to produce anxiolytic-like actions, arousal, and enhance memory consolidation, whereas blockade of the NPSR has been shown to reduce relapse to substances of abuse and duration of anesthetics. We report here the discovery of a novel core scaffold (+) N-benzyl-3-(2-methylpropyl)-1-oxo-3-phenyl-1H,3H,4H,5H,6H,7H-furo[3,4-c]pyridine-5-carboxamide with potent NPSR antagonist activity in vitro. Pharmacokinetic parameters demonstrate that 14b reaches pharmacologically relevant levels in plasma and the brain following intraperitoneal (i.p.) administration, but is cleared rapidly from plasma. Compound 14b was able to block NPS (0.3 nmol)-stimulated locomotor activity in C57/Bl6 mice at 3 mg/kg (i.p.), indicating potent in vivo activity for the structural class. This suggests that 14b can serve as a useful tool for continued mapping of the pharmacological functions of the NPS receptor system.

Simulated Gastric Digestion and In Vivo Intestinal Uptake of Orally Administered CuO Nanoparticles and TiO2 E171 in Male and Female Rat Pups.

Oral exposure to nanoparticles (NPs) during early life is an understudied area. The goals of this study were to evaluate the effect of pre-weaned rat gastric fluids on 50 nm CuO NPs and TiO2 E171 in vitro, and to evaluate uptake in vivo. The NP uptake was studied in vivo in male and female Sprague-Dawley rat pups following oral administration of four consecutive daily doses of 10 mg/kg CuO NPs, TiO2 E171, or vehicle control (water) between postnatal day (PND) 7-10. Rat pups were sacrificed on either PND10 or PND21. Simulated digestion led to dissolution of CuO NPs at the later ages tested (PND14 and PND21, but not PND7). In vivo intestinal uptake of CuO NPs and TiO2 E171 was observed by hyperspectral imaging of intestinal cross sections. Brightfield microscopy showed that the number of immune cells increased in the intestinal tissue following NP administration. Orally administered NPs led to low intestinal uptake of NPs and an increase in immune cells in the small and large intestine, suggesting that oral exposure to NPs during early life may lead to irritation or a low-grade inflammation. The long-term impact of increased immune cells in the intestinal tract during early life is unknown.

Pyrazole Agonist of the Apelin Receptor Improves Symptoms of Metabolic Syndrome in Mice.

Apelin receptor agonism improves symptoms of metabolic syndrome. However, endogenous apelin peptides have short half-lives, making their utility as potential drugs limited. Previously, we had identified a novel pyrazole-based agonist scaffold. Systematic modification of this scaffold was performed to produce compounds with improved ADME properties. Compound 13 with favorable agonist potency (cAMPi EC50 = 162 nM), human liver microsome stability (T1/2 = 62 min), and pharmacokinetic profile in rodents was identified. The compound was tested in a mouse model of diet-induced obesity (DIO) and metabolic syndrome for efficacy. Treatment with 13 led to significant weight loss, hypophagia, improved glucose utilization, reduced liver steatosis, and improvement of disease-associated biomarkers. In conclusion, a small-molecule agonist of the apelin receptor has been identified that is suitable for in vivo investigation of the apelinergic system in DIO and perhaps other diseases where this receptor has been implicated to play a role.

Biodistribution, cardiac and neurobehavioral assessments, and neurotransmitter quantification in juvenile rats following oral administration of aluminum oxide nanoparticles.

Little is known about the uptake, biodistribution, and biological responses of nanoparticles (NPs) and their toxicity in developing animals. Here, male and female juvenile Sprague-Dawley rats received four consecutive daily doses of 10 mg/kg Al2 O3 NP (diameter: 24 nm [transmission electron microscope], hydrodynamic diameter: 148 nm) or vehicle control (water) by gavage between postnatal days (PNDs) 17-20. Basic neurobehavioral and cardiac assessments were performed on PND 20. Animals were sacrificed on PND 21, and selected tissues were collected, weighed, and processed for histopathology or neurotransmitter analysis. The biodistribution of Al2 O3 NP in tissue sections of the intestine, liver, spleen, kidney, and lymph nodes were evaluated using enhanced dark-field microscopy (EDM) and hyperspectral imaging (HSI). Liver-to-body weight ratio was significantly increased for male pups administered Al2 O3 NP compared with control. HSI suggested that Al2 O3 NP was more abundant in the duodenum and ileum tissue of the female pups compared with the male pups, whereas the abundance of NP was similar for males and females in the other tissues. The abundance of NP was higher in the liver compared with spleen, lymph nodes, and kidney. Homovanillic acid and norepinephrine concentrations in brain were significantly decreased following Al2 O3 NP administration in female and male pups, whereas 5-hydroxyindoleacetic acid was significantly increased in male pups. EDM/HSI indicates intestinal uptake of Al2 O3 NP following oral administration. Al2 O3 NP altered neurotransmitter/metabolite concentrations in juvenile rats' brain tissues. Together, these data suggest that orally administered Al2 O3 NP interferes with the brain biochemistry in both female and male pups.

Disposition and metabolism of antibacterial agent, triclocarban, in rodents; a species and route comparison.

Triclocarban is a residue-producing antibacterial agent used in a variety of consumer products. These studies investigated the disposition and metabolism of [14C]triclocarban. In male rats following a single gavage administration of 50, 150, and 500 mg/kg, excretion was primarily via feces (feces, 85-86%; urine, 3-6%) with no apparent dose-related effect. In male rats, 29% of the administered dose was excreted in bile suggesting some of the fecal excretion is from the absorbed dose which was excreted to the intestine via bile. The tissue retention of radioactivity was low in male rats (24 h, 3.9%; 72 h, 0.1%). Disposition pattern following gavage administration of 50 mg/kg in female rats and male and female mice were similar to male rats. Plasma elimination half-life of triclocarban in rats following gavage administration was shorter (∼2 h) compared to that based on total radioactivity (≥9 h) which included all products of triclocarban. Absorption following a single dermal application of 1.5 or 3% was low (≤3%) in rodents. Hydroxylated and conjugated metabolites of triclocarban predominated in bile. In hepatocytes, clearance of triclocarban in mouse and human was similar and was faster than in rat.

Disposition and metabolism of sulfolane in Harlan Sprague Dawley rats and B6C3F1/N mice and in vitro in hepatocytes from rats, mice, and humans.

Sulfolane has been found as a ground water contaminant near refining sites. These studies investigated the in vitro hepatic clearance and in vivo disposition of [14C]sulfolane in rats and mice following a single oral administration (30, 100, or 300 mg/kg) and dermal application (100 mg/kg).[14C]Sulfolane was well-absorbed in male rats following oral administration and excreted extensively in urine (≥93%). Total radioactivity in tissues at 24 and 48 h was ∼7% and <2%. Disposition pattern was similar in female rats and male and female mice at 100 mg/kg oral dose.Dermally applied [14C]Sulfolane (covered dose site, 100 mg/kg) was poorly absorbed in male (∼16%) and female (∼19%) rats; absorption increased to 59% when the dose site was uncovered in male rats suggesting ingestion of dose via grooming of the dose site. Dermally applied [14C]sulfolane (100 mg/kg, covered dose site) was well absorbed in male (∼70%) and female (∼80%) mice.Urinary radiochemical profiles were similar between routes, species, and sexes; the main analytes present in urine were sulfolane and 3-hydroxysulfolane.Sulfolane was not cleared in hepatocytes from rodents or human suggesting sites other than liver might be involved in metabolism of sulfolane in vivo.

Disposition and metabolism of N-butylbenzenesulfonamide in Sprague Dawley rats and B6C3F1/N mice and in vitro in hepatocytes from rats, mice, and humans.

N-Butylbenzenesulfonamide (NBBS) is a plasticizer detected in the environment suggesting potential human exposure. These studies investigated the in vitro hepatic clearance and disposition of [14C]NBBS in rodents following a single gavage (2, 20 or 200 mg/kg) or intravenous (IV) administration (20 mg/kg). NBBS was cleared slower in hepatocytes from humans compared to rodents. [14C]NBBS was well-absorbed in male rats following gavage administration and excreted extensively in urine (70-76 %) and feces (11-15 %) 72 h following administration. Following a 20 mg/kg gavage dose in male rats, 25 % of the dose was excreted in bile by 24 h suggesting that observed fecal excretion was due to biliary excretion. The radioactivity was distributed to tissues with 14 % and 8 % of the administered dose remaining in tissues at 24 and 72 h, respectively. There was no apparent dose-dependent effect in disposition in male rats. Disposition patterns were similar in female rats (urine, 83 %; feces, 14 %) and male (urine, 69 %; feces, 11 %) and female (urine, 72 %; feces, 9 %) mice following gavage administration of 20 mg/kg. The disposition following IV administration was similar to that of gavage. Urinary radiochemical profiles were similar between doses, routes, species, and sexes. Among numerous metabolites identified, oxidative metabolites of NBBS predominated.

Route of administration effects on nicotine discrimination in female and male mice.

BACKGROUND: Use of electronic cigarettes (e-cigarettes) has increased exponentially since their appearance on the U.S. market around 2007. To provide preclinical models of vaping that incorporate olfactory cues and chemosensory effects (including flavors) that play a role in human vaping behavior, the feasibility of using a modified e-cigarette device for delivery of aerosolized nicotine was examined in a nicotine discrimination procedure in mice. METHODS: Adult female and male C57BL/6 mice were trained to discriminate 0.75 mg/kg subcutaneous (s.c.) nicotine from saline. After determination of a s.c. nicotine dose-effect curve, aerosolized freebase nicotine and nicotine-containing tobacco products (i.e., non-flavored and Arctic Blast e-liquids) were evaluated. RESULTS: Nicotine (s.c.) dose-dependently substituted in mice of both sexes, although females showed less sensitivity and greater variability. By contrast, aerosolized nicotine, regardless of formulation, produced concentration-dependent increases up to maximum of 46-62% nicotine-associated responding. Brain nicotine concentrations for each sex were similar for s.c. 0.75 mg/kg nicotine and 30 mg/ml freebase nicotine. CONCLUSIONS: Mice of both sexes readily acquired s.c. nicotine discrimination, but females showed less sensitivity. Further, all three formulations of aerosolized nicotine produced increases in nicotine-like responding in mice of each sex. However, the maximum magnitude of these increases did not engender a similar degree of substitution as s.c. 0.75 mg/kg nicotine, despite similar brain concentrations of nicotine at 30 mg/ml aerosolized nicotine. Additional research is needed for determination of the reason(s); however, results here demonstrate initial feasibility for examination of the discriminative stimulus effects of vaped drugs such as nicotine.

Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor - SAR efforts towards selectivity and peripheralization.

Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (1) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (2) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients including anxiety, depression and suicidal ideation. Currently, efforts are underway to produce compounds that have limited brain penetration. In this report, novel analogs of 1 are explored to develop and test strategies for peripheralization. The piperidine of 1 is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 75 that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. SAR studies revealed ways to adjust physical properties to limit brain exposure.

Functionalized 6-(Piperidin-1-yl)-8,9-Diphenyl Purines as Peripherally Restricted Inverse Agonists of the CB1 Receptor.

Peripherally restricted CB1 receptor antagonists may be useful in treating metabolic syndrome, diabetes, liver diseases, and gastrointestinal disorders. Clinical development of the centrally acting CB1 inverse agonist otenabant (1) was halted due to its potential of producing adverse effects. SAR studies of 1 are reported herein with the objective of producing peripherally restricted analogues. Crystal structures of hCB1 and docking studies with 1 indicate that the piperidine group could be functionalized at the 4-position to access a binding pocket that can accommodate both polar and nonpolar groups. The piperidine is studied as a linker, functionalized with alkyl, heteroalkyl, aryl, and heteroaryl groups using a urea connector. Orally bioavailable and peripherally selective compounds have been produced that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. Compound 38 blocked alcohol-induced liver steatosis in mice and has good ADME properties for further development.

Bisphenol F has different effects on preadipocytes differentiation and weight gain in adult mice as compared with Bisphenol A and S.

Bisphenol S (2,2-bisulfone, BPS) and Bisphenol F (2,2-bis [4-hydroxyphenol]methane, BPF) are analogs of Bisphenol A (2,2-bis[4-hydroxyphenyl]propane, BPA), a widely used endocrine disrupting compound present in polycarbonate plastics, thermal receipts and epoxy resins that line food cans. Here we examined effects of BPA, BPS, and BPF in low concentrations on differentiation in murine 3T3-L1 preadipocytes. We also fed adult male mice chow with one of three doses of BPF (0, 0.5, 5, 50 mg/kg chow, or approximately 0.044, 0.44 and 4.4 mg/kg body weight per day) for 12 weeks, collected body weights, food intake, and tested for glucose tolerance. The doses of BPF used produced mean concentrations of 0, 6.2, 43.6, and 561 ng/mL in plasma. In 3T3-L1 cells BPS had the greatest effects, along with BPA, both increased expression of several genes required for preadipocyte differentiation over 12 days in culture. In contrast, BPF decreased expression of several genes late in differentiation. This dichotomy was also reflected in lipid accumulation as BPA and BPS treated cells had elevated lipid concentrations compared to controls or cells treated with BPF. Male mice fed either the highest or lowest concentrations of BPF gained less weight than controls with no effects on glucose levels or glucose tolerance. Plasma levels of BPF reflected doses in food with no overlap between doses. In summary, our results suggest that BPS has a strong potential to be obesogenic while effects of BPF are subtler and potentially in the opposite direction.

Disposition of tris(4-chlorophenyl)methanol and tris(4-chlorophenyl)methane in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following oral and intravenous administration.

Tris(4-chlorophenyl)methane (TCPME) and tris(4-chlorophenyl)methanol (TCPMOH) have been detected in various biota and human tissues. The current studies were undertaken to investigate the disposition and metabolism of TCPME and TCPMOH in rats and mice. [14C]TCPME was well absorbed (≥66%) in male rats and mice following a single oral administration of 1, 10, or 100 mg/kg. The excretion of [14C]TCPME-derived radioactivity in urine (≤2.5%) and feces (≤18%) was low. The administered dose was retained in tissues (≥ 64%) with adipose containing the highest concentrations. The metabolism of TCPME was minimal. The disposition and metabolism of [14C]TCPME in females was similar to males. The time to reach maximum concentration was ≤7 h, the plasma elimination half-life was ≥31 h, and the bioavailability was ≥82% following a 10 mg/kg oral dose of [14C]TCPME in male rats and mice. The disposition of [14C]TCPMOH was similar to that of [14C]TCPME. Following an intravenous administration of [14C]TCPME or [14C]TCPMOH in male rats and mice, the pattern of disposition was similar to that of oral administration. In conclusion, both TCPME and TCPMOH are readily absorbed and highly bioavailable following a single oral administration pointing to importance of assessing the toxicity of these chemicals.

Metabolism of 4-methylimidazole in Fischer 344 rats and B6C3F1 mice.

4-Methylimidazole (4-MeI) is a widely used chemical, also identified as a by-product of heating foods. In cancer bioassays, 4-MeI induced lung tumors in mice, but not in rats. To establish if metabolic differences could explain species difference in carcinogenicity, this study investigated metabolism of 4-MeI in rat and mouse lung and liver microsomes and S-9 fractions, and in vivo in rats and mice. No metabolites were detected in rat or mouse lung and liver microsomes, or lung S-9 fractions. Male and female F-344 rats and B6C3F1 mice were administered 50 and 150 mg/kg [14C] 4-MeI by gavage. Excreta, exhaled CO2 and volatiles were collected for 48 h. Elimination was mainly via urine, with 79-89% of the radioactivity in urine in rats and 41-70% in mice. Most of the radioactivity (71-88%) in urine was unchanged 4-MeI. Additional radioactive peaks (the largest metabolite was 8-18%) were characterized by LC-MS/MS as 4-hydroxymethylimidazole, its glucuronide, and other oxidized products, including methylhydantoin. 4-MeI was largely excreted unchanged in rats and mice with limited oxidative metabolism and conjugation. 4-MeI was not oxidized in subcellular fractions from rat and mouse lung and liver. Overall, the metabolism of 4-MeI appeared similar between rats and mice.

Synthesis and pharmacological characterization of functionalized 6-piperazin-1-yl-purines as cannabinoid receptor 1 (CB1) inverse agonists.

Antagonists of peripheral type 1 cannabinoid receptors (CB1) may have utility in the treatment of obesity, liver disease, metabolic syndrome and dyslipidemias. We have targeted analogues of the purine inverse agonist otenabant (1) for this purpose. The non-tissue selective CB1 antagonist rimonabant (2) was approved as a weight-loss agent in Europe but produced centrally mediated adverse effects in some patients including dysphoria and suicidal ideation leading to its withdrawal. Efforts are now underway to produce compounds with limited brain exposure. While many structure-activity relationship (SAR) studies of 2 have been reported, along with peripheralized compounds, 1 remains relatively less studied. In this report, we pursued analogues of 1 in which the 4-aminopiperidine group was switched to piperazine group to enable a better understanding of SAR to eventually produce compounds with limited brain penetration. To access a binding pocket and modulate physical properties, the piperazine was functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a variety of connectors, including amides, sulfonamides, carbamates and ureas. These studies resulted in compounds that are potent antagonists of hCB1 with high selectivity for hCB1 over hCB2. The SAR obtained led to the discovery of 65 (Ki = 4 nM, >1,000-fold selective for hCB1 over hCB2), an orally bioavailable aryl urea with reduced brain penetration, and provides direction for discovering peripherally restricted compounds with good in vitro and in vivo properties.

Potent and Selective Tetrahydroisoquinoline Kappa Opioid Receptor Antagonists of Lead Compound (3 R)-7-Hydroxy- N-[(1 S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (PDTic).

Past studies have shown that it has been difficult to discover and develop potent and selective κ opioid receptor antagonists, particularly compounds having potential for clinical development. In this study, we present a structure-activity relationship (SAR) study of a recently discovered new class of tetrahydroisoquinoline κ opioid receptor antagonists which led to (3 R)-7-hydroxy- N-{(1 S)-2-methyl-1-[(-4-methylpiperidine-1-yl)methyl]propyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (12) (4-Me-PDTic). Compound 12 had a Ke = 0.37 nM in a [35S]GTPγS binding assay and was 645- and >8100-fold selective for the κ relative to the µ and δ opioid receptors, respectively. Calculated log BB and CNS (central nervous system) multiparameter optimization (MPO) and low molecular weight values all predict that 12 will penetrate the brain, and pharmacokinetic studies in rats show that 12 does indeed penetrate the brain.