Pharmacological characterization of the influence of deuteration of selected pyrazoloquinolinones as GABAA receptor modulatores

Važno mesto u istraživanjima poslednjih godina zauzimaju GABAA receptori (GABAAR) sa α6podjedinicom u pentamernom receptorskom kompleksu. Ovi receptori imaju potencijalno važnuulogu u razvoju trigeminalnog orofacijalnog bola, migreni, neuropsihijatrijskim poremećajima sasenzorno-motornim deficitima kao što su tikovi, Tourette-ov sindrom, određeni simptomishizofrenije, opsesivno-kompulzivni poremećaj i poremećaji pažnje. Otkriveno je mesto vezivanjana α+β- međupovršini GABAAR označeno kao pirazolohinolinonsko (PQ) mesto, zajedno saprvim α6-selektivnim ligandom, PZ-II-029. Zatim je pronađeno još nekoliko PQ liganada kojideluju kao funkcionalno selektivni pozitivni modulatori na PQ mestu α6 GABAA receptora, dokneutralnu modulaciju ostvaruju posredstvom benzodiazepinskog mesta.Najpre smo sproveli eksperimente farmakokinetičke karakterizacije PQ jedinjenja iz tri strukturnegrupe (PZ-II-029 i srodni deuterisani i/ili nitrogenovani analozi DK-I-56-1, RV-I-029, DK-I-60-3i DK-I-86-1; LAU463 i srodni deuterisani i/ili nitrogenovani analozi DK-I-58-1 i DK-II-58-1; iDK-I-87-1) i još pet dodatnih liganada (jedan koji je meta izomer DK-I-87-1 (DK-I-59-1) i četirifluorirana analoga (DK-IV-19-1, DK-IV-20-1, DK-IV-22-1 i MM-I-10)) nakon intraperitonealne,oralne ili intravenske primene. Osim puta primene, faktor varijacije predstavljala je i formulacija(suspenzija, rastvor ili nanoemulzija) kao i soj životinja (C57BL miševi, Wistar i Sprague-Dawleypacovi). Određena je apsolutna oralna biološka raspoloživost, kao i slobodne frakcije u plazmi imozgu dva liganda (PZ-II-029 i DK-I-56-1). Daljim istraživanjem procenjivali smo uticajnavedenih PQ liganada, samih ili u kombinaciji sa diazepamom, na ponašanje adultnih mužjakapacova Wistar i Sprague-Dawley soja, odnosno miševa C57BL soja. Supstanca DK-I-56-1, kojaje na osnovu prethodnih eksperimenata identifikovana kao vodeća molekula, ispitana je nakonhronične konstrikcione povrede infraorbitalnog živca kao modela trigeminalne neuropatije namužjacima pacova Wistar soja. Primena DK-I-56-1 u animalnom modelu trajala je 14 dana počevod prvog dana nakon operacije, a razvoj bolne preosetljivosti ispitivan je von Frey filamentima udefinisanim vremenskim periodima. Farmakokinetički profili i parametri nedvosmisleno ukazujuna optimizaciju i unapređenje farmakokinetike deuterisanih analoga u plazmi i mozgu, prirazličitim putevima primene, kao i pri različitim formulacijama ispitivanog liganda. Obe strategije,deuteracija i fluorovanje, povećale su metaboličku stabilnost, dok su razlike u farmakokineticiizmeđu deuterisanih i fluorovanih analoga bile izražene. Naime, fluorovani analozi pokazujuznačajno zadržavanje u organima za izlučivanje (jetra i bubreg), a uz podatke da pokazuju izvesnucitotoksičnost in vitro na ćelijskim linijama jetre i bubrega, kao i da su efikasnost i funkcionalnaselektivnost za α6+β3- PQ mesto α6-GABAAR smanjeni u poređenju sa deuterisanim ligandima,čini ih manje pogodnim za dalje faze istraživanja. Dakle, strategija deuteracije pokazala sesuperiornom u odnosu na fluorovanje pirazolohinolinona u smislu održavanja α6-GABAAreceptorske selektivnosti uz povećanje metaboličke stabilnosti i biološke raspoloživosti...GABAA receptors (GABAARs) containing the α6 subunit (α6-GABAARs) have recently obtainedan important place in research. They play a distinct role in trigeminal orofacial pain, migraine, andneuropsychiatric disorders with sensori-motor gating deficits (such as tic disorders, Tourette’ssyndrome, certain symptoms of schizophrenia, obsessive compulsive disorder and attention deficitdisorders). The binding site at the α+β- interface of GABAARs, designated as thepyrazoloquinolinone (PQ) site, was discovered, along with the first α6-selective ligand, PZ-II-029.Subsequent research led to the development of a series of PQs, as functionally selective positivemodulators at the PQ site of α6-containing GABAARs. PQs are also neutral modulators at thebenzodiazepine site.Firstly, we conducted pharmacokinetic characterization of PQs from three structural groups (PZ-II-029 and related deuterated and/or nitrogenated analogs DK-I-56-1, RV-I-029, DK-I-60-3 andDK-I-86-1; LAU 463 and related deuterated and/or nitrogenated analogs DK-I-58-1 and DK-II-58-1; and DK-I-87-1) and five additional ligands (one meta isomer of DK-I-87-1 (DK-I-59-1) andfour fluorinated analogues (DK-IV-19-1, DK-IV-20-1, DK-IV-22-1 and MM-I-10)), afterintraperitoneal, oral or intravenous administration. Beside the route of administration, formulation(suspension, solution or nanoemulsion) and the animal strain (C57BL mice, Wistar and Sprague-Dawley rats) were additional factors of variation. Absolute oral bioavailability, as well asestimated free fractions in plasma and brain of two ligands (PZ-II-029 and DK-I-56-1), weredetermined. Through further research, we evaluated the influence of PQ ligands, alone or incombination with diazepam, on the behavior of adult male Wistar and Sprague-Dawley rats, orC57BL mice. On the basis of previous experiments, DK-I-56-1 was identified as a "lead"compound and tested after chronic constriction injury of the infraorbital nerve as a model oftrigeminal neuropathy in male Wistar rats. The application of DK-I-56-1 in the animal model lastedfor 14 days starting from the first day after surgery, and the development of pain hypersensitivitywas examined with von Frey filaments in defined time periods. Pharmacokinetic profiles andparameters clearly indicate optimization and improvement of pharmacokinetics of deuteratedanalogues in plasma and brain, with different routes of administration, as well as with differentformulations of the investigated ligand. While the strategy of deuteration and fluorinationincreased metabolic stability, the pharmacokinetic influence on plasma, brain, liver and kidneyexposure was dramatically different. Namely, the fluorinated analogues showed significantretention in the excretory organs (liver and kidney). Also, they exhibited a slightly increasedcytotoxic effect on liver and kidney cell lines in vitro. Efficacy and functional selectivity for theα6+β3- interface (PQ site) of α6-GABAARs was reduced for the fluorinated analogs in comparisonto the deuterated ligands. All these facts make them less suitable for further research. Thus, thedeuteration strategy proved superior to fluorination of these PQs in terms of maintaining α6-GABAAR selectivity while enhancing the metabolic stability and bioavailability. These α6-GABAAR ligands were devoid of observable detrimental effects..

Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće

Introduction: Animal models enable the investigation of association between maternal inflammation during pregnancy and different neuropsychiatric disorders in offspring, which has been reported in epidemiological studies. Aim: Investigation of inflammation existence in female rats exposed to LPS during pregnancy and its influence on spatial memory impairment in offspring in Morris water maze. Material and methods: Pregnant Wistar females were exposed to LPS or saline (SAL) at gestational day 15 and 16 and their blood was taken for TNF-α concentration determination. Rats of both sexes (male - M, female - F) went through five-day memory acquisition and one-day memory retrieval test during two periods (35 - 39 postnatal day (P35-39) and P40; likewise P55-59 and P60). We analyzed memory acquisition (latency and path efficiency to platform finding and total distance travelled) and memory retrieval parameters (number of entries and path efficiency to first entry to the target zone). Results: We found higher TNF-α concentration present in LPS-treated dams. There were no significant differences for any of the parameters analyzed for P40 animals and P60 females. M/LPS/P60 rats had a significantly decreased path efficiency to platform finding, increased total distance travelled and a trend of increased latency to platform finding, compared to M/SAL/P60 in the memory acquisition test, and a significantly decreased path efficiency to first entry to the target zone in the memory retrieval test. Conclusion: Lipopolysaccharide (LPS) - induced maternal inflammation during pregnancy leads to spatial memory impairment in male rat offspring in early adulthood, a finding that can be a basis for animal modeling of neurodevelopmental disorders.Uvod: Animalni modeli pružaju mogućnost ispitivanja veze između zapaljenja kod majki tokom trudnoće i različitih neuropsihijatrijskih poremećaja potomstva, pokazane u epidemiološkim studijama. Cilj rada: U ovom radu je ispitivano postojanje zapaljenja kod ženki pacova izloženih LPS-u tokom trudnoće i njegov uticaj na oštećenje prostorne memorije potomstva u Morisovom vodenom lavirintu. Materijal i metode: Gravidne ženke soja Wistar bile su izložene LPS-u ili fiziološkom rastvoru (SAL) 15. i 16. dana gestacije i uzimana im je krv radi određivanja koncentracije TNF-α. Mladunci oba pola (mužjaci - M, ženke - F) podvrgnuti su petodnevnom testu sticanja i jednodnevnom testu pozivanja memorije u dva postnatalna perioda (35 - 39. postnatalnog dana života (P35- 39) i P40, odnosno P55-59 i P60). Analizirani su parametri sticanja (latencija i efikasnost putanje do pronalaska platforme i ukupan pređeni put) i pozivanja prostorne memorije (broj ulazaka i efikasnost putanje do prvog ulaska u ciljnu zonu). Rezultati: Utvrđene su povišene koncentracije TNF-α kod majki tretiranih LPS-om. Kod P40 životinja nije bilo značajnih razlika u praćenim bihejvioralnim parametrima, kao ni kod P60 ženki. Pokazano je da su pacovi M/LPS/P60 imali statistički značajno manju efikasnost putanje do pronalaska platforme, veći ukupni pređeni put i trend povećanja latencije do pronalaska platforme u odnosu na M/SAL/P60 u testu sticanja memorije, kao i značajno manju efikasnost putanje do prvog ulaska u ciljnu zonu u testu pozivanja memorije. Zaključak: Lipopolisaharidom (LPS) izazvano zapaljenje kod ženki pacova tokom trudnoće utiče na oštećenje prostorne memorije kod potomstva muškog pola u ranom odraslom dobu, što bi moglo poslužiti za razvijanje animalnog modela neurorazvojnih oboljenja

Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach

Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain

Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit

We have synthesized and characterized MP-III-022 ((R)-8-ethynyl 6 (2 fluorophenyl)-N,4-dimethyl4H-benzo[f]imidazo[1,5-alpha][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy selective positive allosteric modulator of GABA(A) receptors containing the alpha 5 subunit (alpha 5GABA(A)Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 110 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of alpha 5 beta gamma 2 GABA(A) receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-alpha 5 GABA(A)Rs as well as the desired alpha 5GABA(A)Rs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of alpha 5GABA(A)Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of alpha 5GABA(A)Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism

Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors

gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain

Hydrochloride Salt of the GABAkine KRM-II-81

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 standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1H NMR and 13C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation

Pharmacological characterization of the influence of deuteration of selected pyrazoloquinolinones as GABAA receptor modulatores

Važno mesto u istraživanjima poslednjih godina zauzimaju GABAA receptori (GABAAR) sa α6 podjedinicom u pentamernom receptorskom kompleksu. Ovi receptori imaju potencijalno važnu ulogu u razvoju trigeminalnog orofacijalnog bola, migreni, neuropsihijatrijskim poremećajima sa senzorno-motornim deficitima kao što su tikovi, Tourette-ov sindrom, određeni simptomi shizofrenije, opsesivno-kompulzivni poremećaj i poremećaji pažnje. Otkriveno je mesto vezivanja na α+β- međupovršini GABAAR označeno kao pirazolohinolinonsko (PQ) mesto, zajedno sa prvim α6-selektivnim ligandom, PZ-II-029. Zatim je pronađeno još nekoliko PQ liganada koji deluju kao funkcionalno selektivni pozitivni modulatori na PQ mestu α6 GABAA receptora, dok neutralnu modulaciju ostvaruju posredstvom benzodiazepinskog mesta. Najpre smo sproveli eksperimente farmakokinetičke karakterizacije PQ jedinjenja iz tri strukturne grupe (PZ-II-029 i srodni deuterisani i/ili nitrogenovani analozi DK-I-56-1, RV-I-029, DK-I-60-3 i DK-I-86-1; LAU463 i srodni deuterisani i/ili nitrogenovani analozi DK-I-58-1 i DK-II-58-1; i DK-I-87-1) i još pet dodatnih liganada (jedan koji je meta izomer DK-I-87-1 (DK-I-59-1) i četiri fluorirana analoga (DK-IV-19-1, DK-IV-20-1, DK-IV-22-1 i MM-I-10)) nakon intraperitonealne, oralne ili intravenske primene. Osim puta primene, faktor varijacije predstavljala je i formulacija (suspenzija, rastvor ili nanoemulzija) kao i soj životinja (C57BL miševi, Wistar i Sprague-Dawley pacovi). Određena je apsolutna oralna biološka raspoloživost, kao i slobodne frakcije u plazmi i mozgu dva liganda (PZ-II-029 i DK-I-56-1). Daljim istraživanjem procenjivali smo uticaj navedenih PQ liganada, samih ili u kombinaciji sa diazepamom, na ponašanje adultnih mužjaka pacova Wistar i Sprague-Dawley soja, odnosno miševa C57BL soja. Supstanca DK-I-56-1, koja je na osnovu prethodnih eksperimenata identifikovana kao vodeća molekula, ispitana je nakon hronične konstrikcione povrede infraorbitalnog živca kao modela trigeminalne neuropatije na mužjacima pacova Wistar soja. Primena DK-I-56-1 u animalnom modelu trajala je 14 dana počev od prvog dana nakon operacije, a razvoj bolne preosetljivosti ispitivan je von Frey filamentima u definisanim vremenskim periodima. Farmakokinetički profili i parametri nedvosmisleno ukazuju na optimizaciju i unapređenje farmakokinetike deuterisanih analoga u plazmi i mozgu, pri različitim putevima primene, kao i pri različitim formulacijama ispitivanog liganda. Obe strategije, deuteracija i fluorovanje, povećale su metaboličku stabilnost, dok su razlike u farmakokinetici između deuterisanih i fluorovanih analoga bile izražene. Naime, fluorovani analozi pokazuju značajno zadržavanje u organima za izlučivanje (jetra i bubreg), a uz podatke da pokazuju izvesnu citotoksičnost in vitro na ćelijskim linijama jetre i bubrega, kao i da su efikasnost i funkcionalna selektivnost za α6+β3- PQ mesto α6-GABAAR smanjeni u poređenju sa deuterisanim ligandima, čini ih manje pogodnim za dalje faze istraživanja. Dakle, strategija deuteracije pokazala se superiornom u odnosu na fluorovanje pirazolohinolinona u smislu održavanja α6-GABAA receptorske selektivnosti uz povećanje metaboličke stabilnosti i biološke raspoloživosti...GABAA receptors (GABAARs) containing the α6 subunit (α6-GABAARs) have recently obtained an important place in research. They play a distinct role in trigeminal orofacial pain, migraine, and neuropsychiatric disorders with sensori-motor gating deficits (such as tic disorders, Tourette’s syndrome, certain symptoms of schizophrenia, obsessive compulsive disorder and attention deficit disorders). The binding site at the α+β- interface of GABAARs, designated as the pyrazoloquinolinone (PQ) site, was discovered, along with the first α6-selective ligand, PZ-II-029. Subsequent research led to the development of a series of PQs, as functionally selective positive modulators at the PQ site of α6-containing GABAARs. PQs are also neutral modulators at the benzodiazepine site. Firstly, we conducted pharmacokinetic characterization of PQs from three structural groups (PZ- II-029 and related deuterated and/or nitrogenated analogs DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related deuterated and/or nitrogenated analogs DK-I-58-1 and DK-II- 58-1; and DK-I-87-1) and five additional ligands (one meta isomer of DK-I-87-1 (DK-I-59-1) and four fluorinated analogues (DK-IV-19-1, DK-IV-20-1, DK-IV-22-1 and MM-I-10)), after intraperitoneal, oral or intravenous administration. Beside the route of administration, formulation (suspension, solution or nanoemulsion) and the animal strain (C57BL mice, Wistar and Sprague- Dawley rats) were additional factors of variation. Absolute oral bioavailability, as well as estimated free fractions in plasma and brain of two ligands (PZ-II-029 and DK-I-56-1), were determined. Through further research, we evaluated the influence of PQ ligands, alone or in combination with diazepam, on the behavior of adult male Wistar and Sprague-Dawley rats, or C57BL mice. On the basis of previous experiments, DK-I-56-1 was identified as a "lead" compound and tested after chronic constriction injury of the infraorbital nerve as a model of trigeminal neuropathy in male Wistar rats. The application of DK-I-56-1 in the animal model lasted for 14 days starting from the first day after surgery, and the development of pain hypersensitivity was examined with von Frey filaments in defined time periods. Pharmacokinetic profiles and parameters clearly indicate optimization and improvement of pharmacokinetics of deuterated analogues in plasma and brain, with different routes of administration, as well as with different formulations of the investigated ligand. While the strategy of deuteration and fluorination increased metabolic stability, the pharmacokinetic influence on plasma, brain, liver and kidney exposure was dramatically different. Namely, the fluorinated analogues showed significant retention in the excretory organs (liver and kidney). Also, they exhibited a slightly increased cytotoxic effect on liver and kidney cell lines in vitro. Efficacy and functional selectivity for the α6+β3- interface (PQ site) of α6-GABAARs was reduced for the fluorinated analogs in comparison to the deuterated ligands. All these facts make them less suitable for further research. Thus, the deuteration strategy proved superior to fluorination of these PQs in terms of maintaining α6- GABAAR selectivity while enhancing the metabolic stability and bioavailability. These α6- GABAAR ligands were devoid of observable detrimental effects..

Parenteral nanoemulsions of risperidone for enhanced brain delivery in acute psychosis: Physicochemical and in vivo performances

This work aimed to deepen the lately acquired knowledge about parenteral nanoemulsions as carriers for brain delivery of risperidone, a poorly water-soluble antipsychotic drug, through establishing the prospective relationship between their physicochemical, pharmacokinetic, biodistribution, and behavioral performances. For this purpose, two optimized risperidone-loaded nanoemulsions, stabilized by lecithin or lecithin/polysorbate 80 mixture, and costabilized by sodium oleate, were produced by high-pressure homogenization. The characterization revealed the favorable droplet size, narrow size distribution, high surface charge, with proven stability to autoclaving and long-term stability for at least one year at 25 +/- 2 degrees C. Pharmacokinetic and tissue distribution results demonstrated improved plasma, liver, and brain pharmacokinetic parameters, resulting in 1.2-1.5-fold increased relative bioavailability, 1.1-1.8-fold decreased liver distribution, and about 1.3-fold improved brain uptake of risperidone active moiety following intraperitoneal administration of nanoemulsions relative to solution in rats. In behavioral study, investigated nanoemulsions showed pronounced reduction in basal and, more pertinently, amphetamine-induced locomotor activity in rats, with an early onset of antipsychotic action, and this effect lasted at least 90 min after drug injection. Together, these findings corroborate the applicability of parenteral nanoemulsions as carriers for enhanced brain delivery of risperidone, further suggesting their promise in acute psychosis treatment or other emergency situations