Improved survival with resection after transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma

Three patients with malignant blue nevus are reported-one on the right side of the body, one on the right arm, and one on the face. The criteria and difficulty of histopathological diagnosis are considered as well as the differential diagnoses for this tumor. The therapy is described, and the possible relations between malignant blue nevus and certain other tumors (e.g., atypical or locally aggressive cellular blue nevus) are explored. A review of the literature reveals that there is current disagreement about the exact prognosis for these tumors and indicates the need to collect data for all patients observed.     

Alpha-1-thymosin and transcatheter arterial chemoembolization in hepatocellular carcinoma patients: a preliminary experience

BACKGROUND/AIMS: To evaluate the tolerability and therapeutic potential of the immunostimulating adjuvant alpha-1-thymosin in patients with hepatocellular carcinoma. METHODOLOGY: Twelve patients with hepatocellular carcinoma were treated with alpha-1-thymosin (900 micrograms/m2 subcutaneously twice per week for 6 months) and transcatheter arterial chemoembolization and compared to a historical control group (matched for gender, age, Okuda staging, Child's score, alpha-fetoprotein serum levels and viral infection) treated with transcatheter arterial chemoembolization alone. RESULTS: No severe side effects were recorded in the 2 treatment groups. The combination of alpha-1-thymosin plus transcatheter arterial chemoembolization resulted in a longer survival that reached statistical significance 7 months after the end of treatment (p < 0.05). Patients receiving combined treatment demonstrated a significant increase in peripheral blood mononuclear cells expressing CD3 (p < 0.05) and CD8 (p < 0.025) 3 months after beginning treatment. They also had a significant increase (p < 0.05) in CD16+ and CD56+ cells after 1 month, and a slight reduction in mononuclear cells expressing CD25, a marker for cell activation. No alterations in the response to phytohemagglutinin stimulation were seen during the alpha-1-thymosin treatment. CONCLUSIONS: The absence of toxicity and the favourable effects observed in this open study call for a double blind control study to confirm the efficacy of the combined treatment.     

A prospective randomized administration of 5''-deoxy-5-fluorouridine as adjuvant chemotherapy for hepatocellular carcinoma treated with transcatheter arterial chemoembolization

Surgical microscopy and electrophysiological techniques were used to standardize the nomenclature for the pudendal nerve and sacral plexus according to their somatic axonal composition in the male rat. We conclude that the pudendal nerve is the segment running from the L6-S1 trunk to the sacral plexus, carrying efferent fibers to the coccygeus, internal obturator, ventral and dorsal bulbospongiosus, ischiocavernosus, external anal sphincter, and external urethral sphincter muscles, and afferent fibers from the penis, prepuce, scrotum, and ventral-proximal tail. The sacral plexus is the complex formed by the bridge-like structure connecting the pudendal nerve with the lumbosacral trunk, and two nerve branches emerging from it, one innervating the proximal half of the scrotal skin, and the other innervating the muscles at the base of the penis known as the motor branch. These branches are only considered as a part of the sacral plexus because they integrate axons from both the lumbosacral trunk and pudendal nerve. The gross anatomy of the pudendal nerve and sacral plexus has a main organization that was observed in 70% of cases, whereas the remaining 30% occurred in two variants. This nomenclature is appropriate to describe the pudendal nerve and sacral plexus in studies that involve them being lesioned or electrophysiologically analysed. A main additional finding was that two large afferent branches innervate the scrotum, one the proximal half and the other the distal half. As mentioned above, the proximal branch belongs to the sacral plexus, whereas the distal branch belongs to the pudendal nerve because all its axons travel to the cord via this nerve. Since stimulation or even manipulation of the scrotal branches resulted in the secretion of semen containing spermatozoa, it is suggested that scrotal afferents are involved in some way in the ejaculatory process, a topic that deserves further research.     

A prospective randomized evaluation of a compound of tegafur and uracil as an adjuvant chemotherapy for hepatocellular carcinoma treated with transcatheter arterial chemoembolization

A prospective randomized trial was conducted to evaluate the efficacy of long-term oral administration of low-dose tegafur combined with uracil as an adjuvant chemotherapy, following transcatheter arterial embolization (TAE) in 40 patients with hepatocellular carcinoma (HCC). Forty eligible patients were randomized into two groups: 20 with TAE plus UFT (a compound of tegafur 200 mg and uracil 448 mg per day) and 20 with TAE alone. A good necrosis rate or decrease in size of more than 70% of the original tumor mass was attained in 10 by TAE plus UFT arm and in 12 by TAE arm alone. As for the "responded" patients, there was no significant difference in the time from tumor response to tumor regrowth between the two groups. The appearance rate of ascites and/or encephalopathy in patients with chemotherapy was slightly higher than that in control patients. The median survival time was 22.7 months for TAE plus UFT arm and 28.2 months for TAE arm alone. There was no significant difference in the cumulative survival curves. In conclusion, these results indicated no substantial benefit for this chemotherapy regimen, as an adjuvant therapy for patients with HCC during repeated TAE.     

RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist

The 5-HT2C receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT2A and 5-HT2B selective antagonists have been described. However, no 5-HT2C selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT2C receptors, we have developed a selective 5-HT2C receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pKi = 8.4) and rat (pKi = 8.5) 5-HT2C receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT2C receptor as compared to the 5-HT2A and 5-HT2B receptors. RS-102221 acted as an antagonist in a cell-based microphysiometry functional assay (pA2 = 8.1) and had no detectable intrinsic efficacy. Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats. Surprisingly, RS-102221 failed to reverse the hypolocomotion induced by the 5-HT2 receptor agonist 1-(3-chlorophenyl)piperazine (m-CPP). It is concluded that RS-102221 is the first selective, high affinity 5-HT2C receptor antagonist to be described.     

Effects of iodoproxyfan, a potent and selective histamine H3 receptor antagonist, on alpha 2 and 5-HT3 receptors

We determined the affinity and/or potency of the novel H3 receptor antagonist iodoproxyfan at alpha 2 and 5-HT3 receptors. Iodoproxyfan and rauwolscine (a reference alpha 2 ligand) (i) monophasically displaced 3H-rauwolscine binding to rat brain cortex membranes (pKi 6.79 and 8.59); (ii) facilitated the electrically evoked tritium overflow from superfused mouse brain cortex slices preincubated with 3H-noradrenaline (pEC50 6.46 and 7.91) and (iii) produced rightward shifts of the concentration-response curve (CRC) of (unlabelled) noradrenaline for its inhibitory effect on the evoked overflow (pA2 6.65 and 7.88). In the guinea-pig ileum, iodoproxyfan 6.3 mumol/l failed to evoke a contraction by itself but depressed the maximum of the CRC of 5-hydroxytryptamine (pD'2 5.24). Tropisetron (a reference 5-HT3 antagonist) produced rightward shifts of the CRC of 5-hydroxytryptamine (pA2 7.84). In conclusion, the affinity/potency of iodoproxyfan at H3 receptors (range 8.3-9.7 [1]) exceeds that at alpha 2 receptors by at least 1.5 log units and that at 5-HT3 receptors by at least 3 log units.     

Cognitive implications for H3 and 5-HT3 receptor modulation of cortical cholinergic function: a parallel story

Evidence reviewed in this paper suggests that interactions of histamine with H3 receptors decrease the cholinergic tone in the frontal cortex and the hippocampus. These interactions may be important in learning and memory. Both H3 and 5-HT3 receptors represent targets for pharmacological intervention by exogenous compounds acting as antagonists. Thus, the use of compounds with such properties as either thioperamide (H3 receptor antagonist) or ondansetron (5-HT3 antagonist) may represent a potential therapy to correct the deficits resulting from cholinergic hypofunction.     

Autoradiographic mapping of 5-HT1B- and 5-HT1D receptors in human brain using [3H]alniditan, a new radioligand

[3H]alniditan, a new potent non-indole serotonin 5-HT1B/1D agonist, was used as a radioligand to characterize 5-HT1B and 5-HT1D receptor (previously termed 5-HT1D beta and 5-HT1D alpha) in various regions of the human brain. Quantitative receptor autoradiography was applied for high anatomical resolution and sensitivity. Highest densities of 5-HT1B/1D receptors were found in the substantia nigra and in the globus pallidus. High to moderate densities were measured in the caudate nucleus, putamen, nucleus accumbens, central gray and hippocampal formation. Very low densities were detected in various cortical regions. In the cerebellum no [3H]alniditan binding was detected. Selective 5-HT1B receptor labeling was achieved using [3H]alniditan in the presence of 300 nM of ketanserin (sufficient to block 5-HT1D receptor labeling). The identity of the 5-HT1B binding sites under these conditions was corroborated by the pIC50 of sumatriptan, which corresponded to its affinity for cloned human 5-HT1B receptors expressed in cells. Surprisingly, the distribution of selective 5-HT1B receptor labeling was completely identical to the distribution of labeling of 5-HT1B + 5-HT1D receptors. The present data indicate that [3H]alniditan is a suitable radioligand for measuring 5-HT1B/1D receptor in the human brain and that the 5-HT1B binding sites are predominant in the presently investigated regions of the human brain.     

The efficacy of RS-25259, a long-acting selective 5-HT3 receptor antagonist, for preventing postoperative nausea and vomiting after hysterectomy procedures

We evaluated the safety and efficacy of RS-25259, a potent and long-acting selective 5-HT3 receptor antagonist, for the prevention of postoperative nausea and vomiting (PONV) in women undergoing hysterectomy procedures. In this randomized, double-blind, placebo controlled, dose-ranging study, 218 healthy, consenting women were assigned to one of the six treatment groups: placebo or RS-25259 0.1, 0.3, 1.0, 3.0, or 30 microg/kg. All patients underwent a standardized general anesthetic technique. The study medication was administered i.v. 20-30 min before the end of surgery. During the initial 24-h period after surgery, the incidence of vomiting, the need for rescue antiemetics, the time to the first episode of emesis, and administration of rescue antiemetic medication, as well as a nausea visual analog scale and verbal categorical scale scores were recorded. In addition, recovery times from the end of anesthesia and the incidences of perioperative side effects were noted. Only 30 microg/kg RS-25259 significantly decreased the incidence of vomiting and the requirement for rescue antiemetics. The largest dose of RS-25259 also delayed the time to the first emetic episode and reduced the number of treatment failures. However, no differences were found in the severity of postoperative nausea (versus saline), and postoperative headaches were more common after the administration of RS-25259 0.3-30 microg/kg i.v. In conclusion, RS-25259 30 microg/kg i.v. was effective in reducing the incidence of PONV after major gynecologic surgery, but the occurrence of headaches with the larger doses of RS-25259 is a concern. Implications: RS-25259, a long-acting 5-HT3 antagonist, was effective in reducing postoperative vomiting only at the largest dose studied (30 microg/kg). However, RS-25259 had no antinausea activity, and the larger doses were associated with an increased incidence of headaches in the postoperative period.     

Combination chemotherapy using intravenous nedaplatin (254-S) and intraarterial cisplatin (CDDP) with transcatheter arterial embolization (TAE) for a patient with uterine cervical cancer: a case report

1. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important in the control of body fluid homeostasis, blood pressure (BP) regulation and vascular remodelling. The genes for these peptides may, therefore, be involved in the pathogenesis of genetic hypertension. We have previously described a quantitative trait locus (QTL) for BP in the ANP gene region on rat chromosome 5. We have now assessed the possibility that this QTL lies at the closely linked BNP locus. 2. Intra-arterial BP and heart weight were measured in 12-week-old (n = 207) and 24-week-old (n = 88) F2 rats derived from crosses between Wistar-Kyoto normotensive rats and spontaneously hypertensive rats. We designed polymerase chain reaction primers to amplify a microsatellite in the BNP gene from genomic DNA. Analysis of variance was used for cosegregation analysis. Linkage mapping and localization of QTL was performed using the Mapmaker computer package. 3. A significant correlation was found between genotype for the BNP gene and systolic BP (P < 0.001) in 12-week-old rats. The ANP gene, but not the BNP gene, was associated with systolic BP in 24 week rats. There was no segregation of heart weight with BNP genotype at 12 or 24 weeks of age. The BNP gene mapped approximately 20 cM from the ANP gene in our rat hybrids, away from the previously described QTL. There was evidence for a second BP locus near to but distinct from the BNP gene. 4. These results suggest that BP QTL are present in the natriuretic peptide gene region but that the ANP and BNP genes themselves have no major effect on BP in this cross.     

Binding profile of the novel 5-HT1B/1D receptor antagonist, [3H]GR 125,743, in guinea-pig brain: a comparison with [3H]5-carboxamidotryptamine

The aim of the research was to characterize muscarinic receptors of bovine ciliary muscle and to investigate the desensitization process. The role of protein kinase C was analyzed. The results show that muscarinic receptors of bovine ciliary muscle have the pharmacological characteristics of the M3 subtype. Acute exposure to phorbol esters (1 microM phorbol 12,13-dibutyrate, PDB, or 0.1 microM phorbol 12-myristate 13-acetate, PMA, for 15 and 5 min, respectively) resulted in antagonism of muscarinic receptor-mediated contraction. Long-term pretreatment (18 h) with PMA to down-regulate protein kinase C resulted in potentiation of carbachol-induced contraction, reduction of agonist-induced desensitization and loss of phorbol ester-induced desensitization. Staurosporine (3 microM) and H7 [1-(5-isoquinolinesulfonyl)-2-methyl-piperazine] (1 microM), protein kinase C inhibitors, produced a significant potentiation of the contractile effect of carbachol, reduced the desensitization produced by repeated addition of carbachol and suppressed that induced by phorbol esters. In vitro incubation with carbachol, PDB or PMA did not cause any modification of the binding of labeled [3H]quinuclidinyl benzilate. In vitro incubation with PDB and PMA produced, as expected, a significant translocation of protein kinase C from the cytosol to the membrane. The incubation of the ciliary muscle with carbachol, using the protocol of exposure that induced maximal desensitization of contractile responses, produced a significant redistribution of the enzyme from the cytosol to the membrane. These findings suggest that agonist-induced modulation of functional cholinergic sensitivity in ciliary muscle is correlated, at least partially, to the translocation of protein kinase C from the cytosol to the membrane. The desensitization by phorbol esters is completely due to protein kinase C activation; during the desensitization process, direct modification of the density and affinity of muscarinic receptors is not involved.     

Hepatic transcatheter arterial chemoembolization alternating with systemic protracted continuous infusion 5-fluorouracil for gastrointestinal malignancies metastatic to liver: a phase II trial of the Puget Sound Oncology Consortium (PSOC 1104)

We assessed a regimen of alternating regional and systemic therapy in patients with gastrointestinal malignancies with liver-dominant metastases for feasibility, toxicity, response rate, response duration, patterns of progression, and progression-free and overall survival. Regional therapy comprised selective hepatic transcatheter arterial chemoembolization (TACE) using a suspension of cisplatin and particulate polyvinyl alcohol. This procedure was delivered between cycles of protracted continuous infusion 5-fluorouracil (PCI-5FU) as systemic chemotherapy. Patient eligibility criteria included: (a) having histologically documented adenocarcinoma arising from a gastrointestinal primary site with unresectable liver metastases bidimensionally measurable on computerized tomography scan; (b) age greater than 18 years; and (c) performance status 0-2 (Zubrod). PCI-5FU (250 mg/m2/day) was administered i.v. for 28 days, followed by the first TACE (TACE 1) delivered to the hepatic artery supplying the lobe with the greatest tumor burden. Restaging was performed before TACE 2 and TACE 3, which followed at monthly intervals. PCI-5FU for 21 days was sandwiched between each of the TACE treatments. After the final TACE, maintenance PCI-5FU was given for 28 days of each 35-day cycle until toxicity or progression. Between December 23, 1991, and January 19, 1995, 32 patients were registered in this trial, of whom 27 were eligible; 20 completed one or more treatment cycles and were evaluable for radiographic response. Patients with colorectal liver metastases predominated (74%). Twelve (44%) of 27 patients had failed one or more prior treatment regimens. There were no treatment-related deaths, and hematological and hepatic toxicities were generally manageable and reversible. Two patients, however, developed hepatic abscesses requiring drainage, and one patient developed an infarcted gallbladder, which necessitated cholecystectomy. There were no patients with complete responses; there were 8 (40%) with partial responses, 4 (20%) with minor responses, 2 (10%) with stable disease, and 6 (30%) who progressed on the treatment. The median duration of response for partial responders was 4.2 months (127 days; range, 56-245 days). The median reduction in carcinoembryonic antigen for responders was 87.5%. Two patients underwent subsequent resection of residual metastases; one of them is still alive at 58.4 months follow-up. The predominant site of disease progression was the liver; 25% of the patients progressed in extrahepatic sites. The median overall survival for the whole group is 14.3 months (95% confidence interval, 7.2-16.2). Actuarial overall survival for the whole group at 1 year and 2 years is 57 and 19%, respectively. Alternating systemic PCI-5FU and regional TACE (cisplatin/polyvinyl alcohol) is an active and feasible regimen with manageable toxicities in patients with metastatic gastrointestinal malignancies with liver-dominant disease and merits further investigation. The complications seen were in line with those reported at other specialized centers.     

123I-5-I-R91150, a new single-photon emission tomography ligand for 5-HT2A receptors: influence of age and gender in healthy subjects

5-HT2A receptors have been implicated in the pathophysiology of mood disorders and in the therapeutic effect of the so-called atypical antipsychotics. Recently, a new radioiodinated ligand with high affinity and selectivity for serotonin 5-HT2A receptors, 123iodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl] 5-iodo-2-methoxybenzamide (123I-5-I-R91150), has been developed and has been shown to be suitable for single-photon emission tomography (SPET) imaging. In this study the influence of age and gender on the ligand binding was investigated in normal volunteers. One hundred and fifty MBq of 123I-5-I-R91150 was administered to 26 normal volunteers (13 females and 13 males) with an age range of 23-60 years. SPET imaging was performed with a triple-headed gamma camera. For semi-quantitative analysis, ratios of ligand binding in different regions of interest to the binding in the cerebellum were calculated. Mean ratios of 1.7 were obtained. No gender difference was demonstrated. 5-HT2A binding was shown to decline with age. Over an age range of 40 years a reduction in ligand binding of 42% +/- 7% was found. These results are in agreement w in vitro and positron emission tomography findings of a decline in 5-HT2A receptor binding with age. The findings confirm the suitability of 123I-5-I-R91150 for SPET imaging of 5-HT2A receptors, and highlight the necessity for age-matched controls in clinical studies.     

Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines

The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.     

Two selective 5-HT1A receptor antagonists, WAY-100 635 and NDL-249, stimulate locomotion in rats acclimatised to their environment and alter their behaviour: a behavioural analysis

The aim was to study firstly, the motor effects of a new 5-HT1A antagonist, NDL-249 [(R)-3-(N-cyclopentyl-N-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyra n-5-carboxamide hydrochloride] and of the reference 5-HT1A antagonist WAY-100 635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride], in comparison to the 5-HT1A agonist (+/-)-8-OH-DPAT [(8-hydroxy-2-(di-N-propylamino) tetralin, hereafter 8-OH-DPAT], in rats acclimatised to the automated activity cages; secondly, to study whether the behavioural effects of NDL-249 and 8-OH-DPAT are sensitive to the 5-HT depleting effects of p-chlorophenylalanine (PCPA); thirdly, to characterise the nature of the antagonist-induced activation seen in the automatic activity cages with the aid of a behavioural observation analysis; fourthly, to examine the interaction between the 5-HT1A receptors mediating the behavioural effects and dopamine (DA) receptors. NDL-249 was found to bind in vitro to rat hippocampal 5-HT1A receptors with high affinity and selectivity. In second messenger studies, it was devoid of agonist-like effects. In the locomotor activity studies, each antagonist significantly increased the incidence of horizontal activity, peripheral activity and rearing. 8-OH-DPAT, while significantly increasing peripheral and horizontal activities, decreased the incidence of rearing. PCPA blocked the motor effects of NDL-249 but did not affect those of 8-OH-DPAT. Observational analyses indicated that NDL-249 induced significant increases at one or more doses in sniffing, rearing and locomotion together with a significant reduction in stillness. WAY-100 635 significantly increased the incidence of rearing, intense grooming and vacuous chewing. The significant increases in sniffing, grooming and intense grooming and the significant decrease in stillness induced by the DA D1 agonist, SK&F 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride], were not altered by concomitant pre-treatment with NDL-249. Pre-treatment of rats with either the DA D1 antagonist SCH-23390 (2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol) or the DA D2 antagonist, raclopride, blocked the reduced stillness and increased sniffing and rearing induced by NDL-249. In conclusion, 5-HT1A antagonists including the new selective antagonist, NDL-249, induce mild behavioural activation in rats, which is mediated probably indirectly via DA systems.     

Immunohistochemical evaluation of thymidylate synthase in gastric carcinoma using a new polyclonal antibody: the clinical role of thymidylate synthase as a prognostic indicator and its therapeutic usefulness

BACKGROUND: Before this study was conducted, the clinical and therapeutic significance of immunohistochemical evaluation of thymidylate synthase (TS) in patients with gastric carcinoma had not yet been clarified. METHODS: TS was immunohistochemically evaluated in 134 gastric carcinomas using anti-TS antibody. TS expression, 11 clinicopathologic variables, and survival were studied, and the correlations among them were investigated. RESULTS: The groups with high and low TS levels consisted of 56 and 78 patients, respectively. Granular cytoplasmic staining patterns of tumor cells were produced by immunohistochemical staining of the gastric carcinoma tissues. The grade of TS staining was significantly correlated with three clinicopathologic variables: depth of invasion, peritoneal metastasis, and stage of the carcinoma (P < 0.05). A univariate analysis revealed that the 5-year survival was significantly better for the low TS group than for the high TS group (P < 0.05): 65.2% for the low TS group and 43.2% for the high TS group. The group with high grade TS staining who received chemotherapy because of the advanced stage of their disease had worse prognoses even if they received adjuvant chemotherapy. A multivariate analysis revealed that four variables (peritoneal metastasis, lymphatic invasion, liver metastasis, and TS staining grade) independently contributed to survival (P < 0.05). The hazard ratio for the group with low grade TS staining was 0.464 compared with the group with high grade staining. CONCLUSIONS: The immunohistochemical evaluation of TS using this anti-TS antibody may be clinically and therapeutically useful in determining the prognosis of gastric carcinoma patients.     

2-aminotetralin-derived substituted benzamides with mixed dopamine D2, D3, and serotonin 5-HT1A receptor binding properties: a novel class of potential atypical antipsychotic agents

A new chemical class of potential atypical antipsychotic agents, based on the pharmacological concept of mixed dopamine D2 receptor antagonism and serotonin 5-HT1A receptor agonism, was designed by combining the structural features of the 2-(N,N-di-n-propylamino)tetralins (DPATs) and the 2-pyrrolidinylmethyl-derived substituted benzamides in a structural hybrid. Thus, a series of 35 differently substituted 2-aminotetralin-derived substituted benzamides was synthesized and the compounds were evaluated for their ability to compete for [3H]-raclopride binding to cloned human dopamine D2A and D3 receptors, and for [3H]-8-OH-DPAT binding to rat serotonin 5-HT1A receptors in vitro. The lead compound of the series, 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (12a), displayed high affinities for the dopamine D2A receptor (Ki = 3.2 nM), the dopamine D3 receptor (Ki = 0.58 nM) as well as the serotonin 5-HT1A receptor (Ki = 0.82 nM). The structure-affinity relationships of the series suggest that the 2-aminotetralin moieties of the compounds occupy the same binding sites as the DPATs in all three receptor subtypes. The benzamidoethyl side chain enhances the affinities of the compounds for all three receptor subtypes, presumably by occupying an accessory binding site. For the dopamine D2 and D3 receptors, this accessory binding site may be identical to the binding site of the 2-pyrrolidinylmethyl-derived substituted benzamides.     

Isosteric substitution of Asn5 in antagonists of oxytocin and vasopressin leads to highly selective and potent oxytocin and V1a receptor antagonists: new approaches for the design of potential tocolytics for preterm labor

Substitution of Asn5 in oxytocin (OT) or vasopressin (VP) invariably leads to a dramatic loss of the biological activities of the peptides. Because of this observation, few structure-activity-relationship studies of OT and VP peptides have involved modifications in the 5 position. It is now recognized that peptide agonists and antagonists may use different structural and conformational features in their interactions with the receptors. Our prior studies showed that OT and VP antagonists, unlike the agonists, tolerate amino acid substitutions in the 5 position. This opens new approaches for the design of antagonists. We describe the effects of isosteric replacement of Asn5 by diaminopropionic acid (Dap) or diaminobutyric acid (Dab) in three OT and VP antagonists: (1) the V1a (vasopressor receptor) antagonist d(CH2)5[Tyr(Me)2]AVP; (2) the OT (uterine OT receptor) antagonist d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH29] OVT and (3) three selective OT antagonists, desGly-NH2,d(CH2)5[D-Tyr2, Thr4]OVT, desGly-NH2, d(CH2)5[D-Phe2, Thr4]OVT and desGly-NH2, d(CH2)5- [D-Trp2, Thr4]OVT. The Dap5 and Dab5 substitutions were tolerated remarkably well, with the less isosteric Dap5 substitution leading to a greater retention of anti-OT potency than the Dab5 substitution. Furthermore, the Dap5 and Dab5 and OT and VP antagonist analogues were surprisingly shown to be much more selective than their respective parent compounds. The Dab5 analogue of (1) was devoid of anti-OT activity. The three Dap5 analogues of (3) were devoid of anti-V1a activities. These appear to be the first single-receptor-type-selective OT and VP antagonists discovered to date. These findings could provide new leads for the development of single-receptor-type-selective receptor probes for the localization and characterization of OT and VP receptors and potential selective tocolytics for the treatment of premature labor.