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The GluN2B subunit of NMDA receptors represents a perspective therapeutic target in various CNS pathologies, including epilepsy. Because of its predominant expression in the immature brain, selective GluN2B antagonists are expected to be more effective early in postnatal development. The aim of this study was to identify age-dependent differences in the anticonvulsant activity of the GluN2B-selective antagonist Ro 25-6981 and assess the safety of this drug for the developing brain. Anticonvulsant activity of Ro 25-6981 (1, 3, and 10 mg/kg) was tested in a pentylenetetrazol (PTZ) model in infantile (12-day-old, P12) and juvenile (25-day-old, P25) rats. Ro 25-6981 (1 or 3 mg/kg/day) was administered from P7 till P11 to assess safety for the developing brain. Animals were then tested repeatedly in a battery of behavioral tests focusing on sensorimotor development, cognition, and emotionality till adulthood. Effects of early exposure to Ro 25-6981 on later seizure susceptibility were tested in the PTZ model. Ro 25-6981 was effective against PTZ-induced seizures in infantile rats, specifically suppressing the tonic phase of the generalized tonic–clonic seizures, but it failed in juveniles. Neither sensorimotor development nor cognitive abilities and emotionality were affected by early-life exposure to Ro 25-6981. Treatment cessation did not affect later seizure susceptibility. Our data are in line with the maturational gradient of the GluN2B-subunit of NMDA receptors and demonstrate developmental differences in the anti-seizure activity of the GluN2B-selective antagonist and its safety for the developing brain.

Using the previously obtained first dipeptide ligand TSPO the N‑carbobenzoxy-L‑tryptophanyl-L‑isoleucine amide (GD‑23) as a basis, the new dipeptide was synthesized — the N‑phenylpropionyl–L‑tryptophanyl-L‑leucine amide (GD‑102). GD‑102 expressed anxiolytic activity in the open field test in BALB/c mice and in the elevated plus maze test in ICR mice. The minimum effective dose of GD‑102 was an order of magnitude lower than that of GD‑23. Preliminary administration of the TSPO selective antagonist, compound PK11195, completely blocked the anxiolytic activity of GD‑102, that indicated the participation of TSPO in the realization of the anxiolytic action GD‑102. The results were confirmed by molecular docking data.

Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:21 issue:14 ispartof: location:Switzerland status: published

Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of memory (i.e., amnesia). Such drug-induced post-reactivation amnesia has traditionally been studied in AAA experimental designs, where a memory is initially created for a stimulus A (be it a singular cue or a context) and later reactivated and tested through exposure to the exact same stimulus. Using a contextual fear conditioning procedure in rats and midazolam as amnestic agent, we recently demonstrated that drug-induced amnesia can also be obtained when memories are reactivated through exposure to a generalization stimulus (GS, context B) and later tested for that same generalization stimulus (ABB design). However, this amnestic intervention leaves fear expression intact when at test animals are instead presented with the original training stimulus (ABA design) or a novel generalization stimulus (ABC design). The underlying mechanisms of post-reactivation memory malleability and of MDZ-induced amnesia for a generalization context remain largely unknown. Here, we evaluated whether, like typical CS-mediated (or AAA) post-reactivation amnesia, GS-mediated (ABB) post-reactivation amnesia displays key features of a destabilization-based phenomenon. We first show that ABB post-reactivation amnesia is critically dependent on prediction error at the time of memory reactivation and provide evidence for its temporally graded nature. In line with the known role of GluN2B-NMDA receptor activation in memory destabilization, we further demonstrate that pre-reactivation administration of ifenprodil, a selective antagonist of GluN2B-NMDA receptors, prevents MDZ-induced ABB amnesia. In sum, our data reveal that ABB MDZ-induced post-reactivation amnesia exhibits the hallmark features of a destabilization-dependent phenomenon. Implication of our findings for a reconsolidation-based account of post-reactivation amnesia are discussed. ispartof: Progress In Neuro-Psychopharmacology & Biological Psychiatry vol:108 pages:1-14 ispartof: location:England status: published

Aim: AZD9496 is an oral nonsteroidal, potent and selective antagonist and degrader of ER-α. Two major active metabolites (M3 and M5 as diastereomers) were identified in humans. Methodology/results: Multianalyte, sensitive LC–MS/MS method in human plasma was developed and validated that overcame the challenges encountered. The method demonstrated acceptable precision, accuracy and selectivity for AZD9496 and two major metabolites. Incurred sample reanalysis was acceptable from evaluation in clinical studies, indicating adequate reproducibility. In addition, a urine method for AZD9496 was also developed and validated. Conclusion: Robust and sensitive LC–MS/MS assays for the quantitation of AZD9496 and two diastereomeric metabolites in human plasma and AZD9496 in human urine have been validated and successfully applied to clinical studies.

We are exploring constraining aromatic residues in the kappa opioid receptor selective antagonist arodyn (Ac[Phe(1,2,3),Arg(4),D-Ala(8)]dynorphin A(1–11)-NH(2)) by ring closing metathesis (RCM) involving tyrosine(O-allyl) (Tyr(All)), but desallyl products limited the yields of the desired cyclic peptide. The model dipeptide Fmoc-Tyr(All)-Tyr(All) was used to explore different reaction conditions, including the use of isomerization suppressants, to minimize formation of the desallyl products and enhance formation of the desired RCM product. Reaction conditions were identified that enhanced the RCM product yield while suppressing desallyl products using both second-generation Grubbs and second-generation Hoveyda Grubbs catalysts. These optimized reaction conditions were then applied to the cyclization of a tripeptide and an arodyn analog resulting in ≥70% conversion to the desired cyclic peptides. These strategies should be applicable to RCM involving Tyr(All) and similar residues in peptide and peptidomimetic cyclizations performed on solid phase.

Background Methamphetamine abuse has increased significantly in recent years. Currently, there are no FDA-approved pharmacotherapies for the treatment of methamphetamine use disorder. The goal of the current study was to determine if the N-methyl- d -aspartate (NMDA) GluN2B-selective antagonist Ro 63-1908 can block the conditioned rewarding effects of methamphetamine as assessed in conditioned place preference (CPP). Methods Two main experiments were conducted. In the first experiment, male (n = 24) and female (n = 24) rats received either vehicle or Ro 63-1908 (1.0–10.0 mg/kg) 30 min prior to the posttest to determine if blocking the GluN2B subunit attenuates expression of methamphetamine CPP. In the second experiment, male (n = 18) and female (n = 18) rats received either vehicle or Ro 63-1908 (1.0 or 3.0 mg/kg) 30 min prior to each conditioning session to determine if blocking the GluN2B subunit attenuates acquisition of methamphetamine CPP. Results Ro 63-1908 (3.0 mg/kg) blocked acquisition of methamphetamine CPP in male rats, but only attenuated CPP in female rats. Ro 63-1908 did not alter expression of CPP in either sex. Increasing the dose of Ro 63-1908 (10.0 mg/kg) failed to block acquisition of CPP in an additional group of female rats (n = 6). A control experiment showed that Ro 63-1908 (3.0 mg/kg) did not produce CPP or conditioned place aversion in male rats (n = 6) or in female rats (n = 6). Conclusions The results of this study show that Ro 63-1908 is able to decrease the conditioned rewarding effects of methamphetamine.

MK 3814 is a potent and selective antagonist of the A2a receptor. A2a receptor antagonists have the potential for the treatment of Parkinson disease. Three distinct isotopically labelled forms of MK 3814 were synthesized. [3 H]MK 3814 was prepared for a preliminary absorption, distribution, metabolism, and excretion data (ADME) evaluation of the compound and [14 C]MK 3814 for more definitive ADME work, including an absorption, metabolism, and excretion study in man. In addition, [2 H4 ]MK 3814 was prepared as an internal standard for a liquid chromatography mass spectrometry bioanalytical method. This paper discusses the synthesis of 3 isotopically labelled forms of MK 3814.

INTRODUCTION AND OBJECTIVES:Renal cell carcinoma (RCC) has the third highest mortality rate among all urological tumors, and 20-30% of RCC patients present with metastatic RCC at the time of diagno...

Kissorphin (KSO) is a new peptide derived from kisspeptin-10. Previous study has indicated that this peptide displays neuropeptide FF (NPFF)-like anti-opioid activity. Herein, we examined the influence of KSO (1; 3, and 10 nmol, intravenously [i.v.]), on the rewarding action of morphine (5 mg/kg, intraperitoneally [i.p.]), using the unbiased design of the conditioned place preference (CPP) paradigm in rats. To test the effect of KSO on the acquisition of morphine-induced CPP, KSO and morphine were co-injected during conditioning with no drugs treatment on the test day. To investigate the effect of KSO on the expression of morphine-induced CPP, morphine alone was given during the conditioning phase (1 × 3 days) and KSO was administered 5 min prior to the placement in the CPP apparatus on the test day. To estimate the influence of KSO on the reinstatement of morphine-induced CPP, KSO was given 5 min before a priming dose of morphine (5 mg/kg, i.p.) on the reinstatement test day. The results show that KSO inhibited the acquisition, expression and reinstatement of morphine-induced CPP. The strongest effect of KSO was observed at the dose of 10 nmol (acquisition and reinstatement) or 1 nmol (expression). KSO given alone, neither induced place preference, nor aversion. Furthermore, the morphine-modulating effects of KSO were markedly antagonized by pretreatment with RF9 (10 nmol, i.v.), the NPFF receptors selective antagonist. Thus, KSO inhibited the morphine-induced CPP mainly by involving specific activation of NPFF receptors. Overall, these data further support the anti-opioid character of KSO.

PPARδ is highly expressed in skin, especially keratinocytes, and its expression is increased in psoriatic lesions. However, the potential role of PPARδ in the pathogenesis of psoriasis remains undefined. Mice treated with Imiquimod (IMQ) to induce psoriasis can be used to evaluate the pathogenesis of psoriasis, and this model has become one of the most important in vivo research tools for research on the disease. In the current study, we showed that PPARδ was highly expressed in the skin of IMQ-induced psoriasis mice. To further understand the impact of PPARδ in psoriasis, we used these mice in a series of experiments to evaluate the pathogenesis of psoriasis. We found that PPARδ was highly expressed in both psoriatic lesions and normal skin in IMQ-induced psoriasis mice. Furthermore, the expression of PPARδ-relevant lipases was also significantly increased. The PPARδ-selective antagonist GSK3787 ameliorated the observed inflammation in the skin of the experimental mice. Based on these results, PPARδ may be a potential target for the effective treatment of psoriasis.

Vicriviroc or SCH 417690 is a potent and selective antagonist of the CCR5 receptor. CCR5 receptor antagonists have the potential for the treatment of HIV infections. Four distinct isotopically labelled forms of SCH 417690 were synthesized. Low specific activity [(3) H]SCH 417690 was prepared for a preliminary absorption, distribution, metabolism and excretion evaluation of the compound and [(14) C]SCH 417690 for more definitive absorption, distribution, metabolism and excretion work, including an absorption, metabolism and excretion study in man. In addition, high specific activity [(3) H]SCH 417690 was prepared for CCR5 receptor binding work and [(2) H4 ]SCH 417690 was prepared as an internal standard for a liquid chromatography-mass spectrometry bioanalytical method. The paper discusses the synthesis of four isotopically labelled forms of SCH 417690.

Выполнен радиолигандный анализ взаимодействия новых оригинальных соединений группы 1-арилпирроло[1,2-a]пиразин-3-карбоксамидов с митохондриальным транслокаторным белком (МТБ) 18 кДа. Показано высокое сродство соединений ГМЛ-1 (Ki = 5,2 · 10 – 8 M) и ГМЛ-3 (Ki = 5,3 · 10 – 7 M) с МТБ 18 кДа. Установлена анксиолитическая активность соединений ГМЛ-1 и ГМЛ-3 в диапазоне доз 0,1 – 1 мг/кг в тесте «приподнятый крестообразный лабиринт» у мышей CD-1, опосредованная рецепторным участком МТБ 18 кДа. Полученные данные о молекулярной мишени, анксиолитических свойствах и низкой токсичности соединений ГМЛ-1 и ГМЛ-3 демонстрируют их высокий потенциал для дальнейшего изучения в качестве анксиолитиков.

e15209 Background: Balixafortide (B) is a potent, selective antagonist of the chemokine receptor CXCR4. High CXCR4 levels correlate with aggressive metastatic phenotypes and poor prognosis in metastatic breast cancer (MBC). Efficacy and safety data were published recently from the Phase 1 trial investigating B + eribulin (E) in patients with HER2 negative MBC1. We report the final efficacy analyses from this trial, including assessment of dose-response. Methods: In this single-arm, dose escalation trial, patients (pts) received E + increasing doses of B using a 3+3 design in 3 parts: Part I (cohorts received low E doses); Part II (dose-escalation cohort for B [1−5.5mg/kg] + 1.4mg/m2 E); Expanded Cohort (EC; 5.5mg/kg B + 1.4mg/m2 E) to confirm safety and efficacy. Results: At entry, all 56 women (age range 33−82 years) were HER2-negative (IHC and/or FISH), CXCR4 positive. The majority were Caucasian. Most pts were heavily pre-treated in the metastatic setting (line of chemotherapy on study: 29% 2nd line, 50% 3rd line, 21% 4th line). 75% were hormone receptor positive and 23% had triple negative breast cancer. Conclusions: A consistent dose response effect for B + E was suggested in heavily pretreated pts with HER2 negative MBC across all efficacy endpoints. A comparison of these efficacy results, and particularly response data, with single agent data for E in similar populations2, 3 showed that pts in the EC had a more profound benefit observed consistently throughout all efficacy endpoints. Further data and analysis will be forthcoming for presentation. 1. 3 patients from Part II also included in EC because they received the B dose selected for EC (5.5mg/kg). 2. Part I was an initial safety run-in with lower E doses, and so is not included in the table. 1. Pernas S et al. Lancet Oncol. 2018; 19: 812−24 2. Cortes J et al. Lancet. 2011; 377: 914−923 3. Kaufman PA et al. J Clin Oncol. 2015; 33: 594−601. Clinical trial information: NCT01837095 . [Table: see text]

Background: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder. Aims: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires. Results: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) −18.8 (21.3) and −29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) −11.1 (36.4) and −11.3 (46.5). The most common adverse events were headache and somnolence. Conclusions: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.

Background/aim The neurokinin 3 receptor (NK-3R) is differentially expressed in the central nervous system including cases of human oral squamous cell carcinoma. However, the role of NK-3R signaling in oral squamous cell carcinoma is not well known. Materials and methods NK-3R expression in surgically resected oral squamous cell carcinoma was examined immunohistochemically and the strength of the expression was quantified. We evaluated the function of NK-3R signaling using NK-3R antagonist in human oral squamous cell carcinoma bone invasion mouse model. Results NK-3R was significantly expressed in tumor cells that had invaded the bone matrix compared to the oral side tumor cells. SB222200, a selective antagonist of NK-3R, significantly suppressed the radiographic osteolytic lesion and tumorigenesis. Conclusion NK-3R signaling is a potential target for the treatment of oral squamous cell carcinoma in cases of bone destruction.

Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity via elevation of endocannabinoids. Primary vagal ganglia neurons, tissue bioassay, in vivo electrophysiology and a conscious guinea pig cough model were utilised to investigate a role for fatty acid amides in modulating sensory nerve activation in vagal afferents. FAAH inhibition produced antitussive activity in guinea pigs with concomitant plasma elevation of the fatty acid amides N-arachidonoylethanolamide (anandamide), palmitoylethanolamide, N-oleoylethanolamide and linoleoylethanolamide. Palmitoylethanolamide inhibited tussive stimulus-induced activation of guinea pig airway innervating vagal ganglia neurons, depolarisation of guinea pig and human vagus, and firing of C-fibre afferents. These effects were mediated via a cannabinoid CB2/Gi/o-coupled pathway and activation of protein phosphatase 2A, resulting in increased calcium sensitivity of calcium-activated potassium channels. These findings identify FAAH inhibition as a target for the development of novel, antitussive agents without the undesirable side-effects of direct cannabinoid receptor agonists.

Background Brain α2- and β-adrenoceptor alterations have been suggested in suicide and major depressive disorder. Methods The densities of α2-, β1- and β2-adrenoceptors in postmortem prefrontal cortex of 26 subjects with depression were compared with those of age-, gender- and postmortem delay-matched controls. The effect of antidepressant treatment on α2- and β-adrenoceptor densities was also evaluated. α2- and β-adrenoceptor densities were measured by saturation experiments with respective radioligands [3H]UK14304 and [3H]CGP12177. β1- and β2-adrenoceptor subtype densities were dissected by means of β1-adrenoceptor selective antagonist CGP20712A. Results Both, α2- and β1-adrenoceptors densities were higher in antidepressant-free depressed subjects (n=14) than those in matched controls (Δ~24%, p=0.013 and Δ~20%, p=0.044, respectively). In antidepressant-treated subjects (n=12), α2-adrenoceptor density remained increased over that in controls (Δ~20%), suggesting a resistance of α2-adrenoceptors to the down-regulatory effect of antidepressants. By contrast, β1-adrenoceptor density in antidepressant-treated depressed subjects was not different from controls, suggesting a possible down-regulation by antidepressants. The down-regulation of β1-adrenoceptor density in antidepressant-treated depressed subjects differs from the unaltered β1-adrenoceptor density observed in citalopram-treated rats and in a group of non-depressed subjects also treated with antidepressants (n=6). β2-adrenoceptor density was not altered in depressed subjects independently of treatment. Limitations Antidepressant-treated subjects had been treated with a heterogeneous variety of antidepressant drugs. The results should be understood in the context of suicide victims with depression. Conclusions These results show the up-regulation of brain α2- and β1-adrenoceptors in depression and suggest that the regulation induced by chronic antidepressant treatment would be altered in these subjects.

Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists.

By natural product inspired diversity-oriented synthesis, we had developed a new class of selective antagonist, IKM-159, for the AMPA receptor. Here, we report syntheses of IKM-159 and skeletally diverse five analogues in racemic forms, two of which are heterotricycles and the other three compounds are truncated analogues, to study the structure–activity relationships. The key reactions are two domino reactions including Ugi/Diels–Alder reaction and domino metathesis reaction. An exceptionally high level of regiocontrol in the cross metathesis reaction is also reported.

Montelukast 1 is a famous drug demonstrated for the chronic and prophylaxis therapy of asthma. It behaves as a selective antagonist of the leukotriene D4 receptor which causes the decrease of broncho constriction and eventuates in less inflammation. Montelukast is prescribed orally once daily which gives a profit in contrast with other drugs for pulmonary diseases such as asthma. The low stability and complex synthesis of Montelukast 1 present multitude difficulties for its large-scale production. Our present study demonstrates a novel and the industrially scalable process for the preparation of sodium (S,E)-2-(1-(((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(methoxycarbonyl)phenyl)propyl)thio)methyl)cyclopropyl)acetate which is one of the key intermediates of the Montelukast sodium synthesis process. We demonstrated a novel process that resolves multitude prior limitations and problems. Our modified process (see in scheme 2), which details are shown in this paper, is appropriate for large-scale production of the active pharmaceutical ingredient (API) with many benefits generally known as Montelukast.

[Phe 1 -psi-(CH 2 NH)-Gly 2 ]-Nociceptin-(1-13)-NH 2 is a pseudopeptide that was synthesized in an attempt to develop a selective antagonist for the target, ORL1, now known as the Nociceptin/Orphanin FQ peptide (NOP) receptor. Though the pseudopeptide appears to be a NOP receptor antagonist in some preparations, it exhibits partial or full agonist activity at that receptor in other preparations.

Commercial whole-body plethysmography systems used to evaluate the anti-tussive potential of drugs employ sophisticated technology, but these systems may be cost prohibitive for some laboratories. The present study describes an alternative, inexpensive system for evaluating the tussive and anti-tussive potential of drugs in conscious, unrestrained guinea pigs.The system is composed of a transparent small animal anesthesia induction box fitted with a microphone, a camera and a pneumotachometer to simultaneously capture audio, video, air flow and air pressure in real time. Data acquisition and analysis was performed using free software for audio and video, and a research pneumotach system for flow and pressure. System suitability testing was performed by exposing conscious, unrestrained guinea pigs to nebulized aqueous solutions of a selective agonist for TRPV1 (citric acid) or a selective agonist for TRPA1 (AITC), with or without pre-treatment with a selective antagonist for TRPV1 (BCTC) or a selective antagonist for TRPA1 (HC-030031).The system easily discerned coughs from other respiratory events like sneezes. System suitability test results are as follows: AITC caused 10.7 (SEM=1.4592) coughs vs. 5.8 (SEM=1.6553) when pre-treated with HC-030031 (P0.05). Citric acid caused 12.4 (SEM=1.4697) coughs vs. 3.2 (SEM=1.3928) when pre-treated with BCTC (P0.002).We have described in detail an inexpensive system for evaluating the tussive and anti-tussive potential of chemicals in conscious, unrestrained guinea pigs. Suitability testing indicates that the system is comparable to a commercial whole-body plethysmography system for detecting and differentiating between coughs and sneezes. This system may provide some investigators a cost-conscious alternative to more expensive commercial whole-body plethysmography systems.

Prazosin hydrochloride is the first developed selective antagonist for 1 – adrenoceptors, which is used as antihypertensive agent. Statins are used in the treatment of various types of hypercholesterolemia. In the present paper a simple, specific an accurate RP-HPLC method was developed and validated for the simultaneous determination of prazosin, atorvastatin, rosuvastatin and simvastatin in active and in dosage formulations. Anucleosil100-10, C-18, 10column having 250 4.6 mmi.d. in isocratic mode, with mobile phase containing methanol:water:acetonitrile (70:20:10) adjusted to pH 2.5 ± 0.02 using orthophosphoric acid. The flow rate was 1 mLmin -1 and effluents were monitored at 240 nm. The % recovery for all thedrugsin formulationswasfound to be94-105%.Theparameterssuch asaccuracy(%RSD lessthan 2), precision (%RSD less than 2), linearity (>0.999) were found to be satisfactory. The presented method was applied without any interference of excepients for the determination of tablets. The proposed method due to its low LOQ, excellent accuracy, precision and selectivity could be used for routine quality control.

Hemopressin, a bioactive nonapeptide derived from the α1 chain of hemoglobin, was recently shown to possess selective antagonist activity at the cannabinoid CB(1) receptor [Heimann, A. S., et al. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 20588-20593]. CB(1) receptor antagonists have been extensively studied for their possible therapeutic use in the treatment of obesity, drug abuse, and heroin addiction. In particular, many compounds acting as CB(1) receptor antagonists have been synthesized and subjected to experiments as possible anti-obesity drugs, but their therapeutic application is still complicated by important side effects. Using circular dichroism and nuclear magnetic resonance spectroscopy, this work reports the conformational analysis of hemopressin and its truncated, biologically active fragment hemopressin(1-6). The binding modes of both hemopressin and hemopressin(1-6) are investigated by molecular docking calculations. Our conformational data indicate that regular turn structures in the central portion of hemopressin and hemopressin(1-6) are critical for an effective interaction with the receptor. The results of molecular docking calculations, indicating similarities and differences in comparison to the most accepted CB(1) pharmacophore model, suggest the possibility of new chemical scaffolds for the design of new CB(1) antagonist lead compounds.