Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists

The structures of ketanserin (1) and spiperone (2) were examined in detail to determine the role of various substituent groups on 5-HT(2A) receptor affinity and selectivity. It was found that the presence of the quinazoline ring of ketanserin detracts from selectivity and that various ring-opened analogs displayed ketanserin-like affinity and up to 30-fold enhanced selectivity. The triazaspirodecanone portion of spiperone is a major determinant of its 5-HT affinity and selectivity. The conformational rigidity imposed by the ring, as well as the nature of the N(1)-substituent, are important factors in controlling binding at 5-HT(2A), 5-HT(2C), 5-HT(1A), and dopamine D2 receptors. Replacement of the N(1)-phenyl ring of spiperone with a methyl group (KML-010; 48) resulted in a compound that binds at 5-HT(2A) receptors with slightly lower affinity than spiperone, but that lacked affinity (Ki >10,000 nM) for 5-HT(2C) and 5-HT(1A) receptors and binds with 400-fold reduced affinity at D2 receptors.     

Stimulus effects of three sulfur-containing psychoactive agents

Two agents gaining popularity on the illicit drug market are the phenylalkylamines 4-MTA and 2C-T-7 [or 1-(4-methylthiophenyl)-2-aminopropane and 2-(2,5-dimethoxy-4-n-propylthiophenyl)-1-aminoethane, respectively]. At this time, there exists a paucity of information on the behavioral actions of these sulfur-containing agents. The present investigation examined these agents, and the N-monomethyl analog of 4-MTA (i.e., 4-MTMA), in tests of stimulus generalization (substitution) using a two-lever drug discrimination task with groups of rats trained to discriminate either the hallucinogen DOM [1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane], the stimulant cocaine, or the empathogen MDMA from vehicle. 4-MTA and its N-monomethyl analog 4-MTMA (ED50 = 0.8 mg/kg in both cases) substituted only for the MDMA stimulus, whereas 2C-T-7 (ED50 = 0.8 mg/kg) substituted only for the DOM stimulus. Thus, at the doses examined, 4-MTA and 4-MTMA appear to be MDMA-like agents, and 2C-T-7 seems best classified as a DOM-like hallucinogen. These results provide additional data that extend the structure-activity relationships of phenylalkylamines and that are consistent with what little is currently known about the action of 4-MTA and 2C-T-7 in humans.     

Impact of incomplete plan to treatment results of concurrent weekly cisplatin and radiotherapy in locally advanced cervical cancer

To evaluate the efficacy of incomplete treatment protocols of cisplatin in concurrent chemoradiation for locally advanced cervical carcinoma. This retrospective study was performed in 165 consecutively treated patients with locally advanced cervical cancer who received a weekly cisplatin regimen. The number of weekly cisplatin cycles of each patient was recorded and used to discriminate between patients. Local control, disease free survival, distant metastasis-free survival, and toxicities were calculated using the software package SPSS version 15.0. Ninety-two patients (55%) completed the planned protocol of six cycles of weekly cisplatin. With the median follow-up time of 38.2 months, the 3-year local control rate differed significantly in the two patient groups (95.4% of 6 cycles versus 84.8% of < 6 cycles; p = 0.028). No statistical significance was observed for disease-free survival (74.6% versus 74.5%; p = 0.22) and distant metastasis-free survival (76.5% vs. 75.7%; p = 0.88). In conclusion, the plan completion of concurrent cisplatin with radiotherapy was responsible for better local control. However, differences in disease-free survival and distant metastasis-free survival were not statistical significant.     

Randomized phase III trial of concurrent chemoradiotherapy vs accelerated hyperfractionation radiotherapy in locally advanced head and neck cancer

The aim of this study was to compare the efficacy and safety of concurrent chemoradiotherapy (CCRT) vs accelerated hyperfractionation with concomitant boost (CCB) as a primary treatment for patients with Stage III–IV squamous cell carcinoma of head and neck (SCCHN). A total of 85 non-metastatic advanced SCCHN patients were accrued from January 2003 to December 2007. Of these, 48 and 37 patients received CCRT and CCB, respectively. The patients were randomized to receive either three cycles of carboplatin and 5-fluorouracil plus conventional radiotherapy (CCRT, 66 Gy in 6.5 weeks) or hybrid accelerated radiotherapy (CCB, 70 Gy in 6 weeks). The primary endpoint was determined by locoregional control rate. The secondary endpoints were overall survival and toxicity. With a median follow-up of 43 months (range, 3–102), the 5-year locoregional control rate was 69.6% in the CCRT arm vs 55.0% in the CCB arm (P = 0.184). The 5-year overall survival rate was marginally significantly different (P = 0.05): 76.1% in the CCRT arm vs 63.5% in the CCB arm. Radiotherapy treatment interruptions of more than three days were 60.4% and 40.5% in the CCRT arm and CCB arm, respectively. The median total treatment time was 55.5 days in the CCRT arm and 49 days in the CCB arm. The rate of Grade 3–4 acute mucositis was significantly higher in the CCB arm (67.6% vs 41.7%, P = 0.01), but no high grade hematologic toxicities were found in the CCB arm (27.2% vs 0%). CCRT has shown a trend of improving outcome over CCB irradiation in locoregionally advanced head and neck cancer.     

Evaluation of a new lead for acetylcholinesterase inhibition

Acetylcholine is the most common neurotransmitter of the parasympathetic nervous system. Several cholinergic drugs are widely used in Alzheimer’s disease, urinary retention, glaucoma, and myasthenia gravis. Acetylcholinesterase is the enzyme which destroys naturally occurring acetylcholine, and acetylcholinesterase inhibitors (AChEIs) which block the enzyme are currently used in the treatment of several diseases, most importantly Alzheimer’s disease. Previous studies from our laboratory have shown a few isoquinoline analogs to be potential acetylcholinesterase inhibitors. In the present study we have extended analysis of the structure–activity relationship (SAR) of the isoquinoline ring system as an AChEI. The corresponding reduced form of 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, ring-opened analog, and related analogs were evaluated for AChE inhibitory activity. Our results showed that the dihydroisoquinoline ring analog compound 6 (IC₅₀ = 7.0 ± 1.4 μM) and compound 4 (IC₅₀ = 5.5 ± 1.0 μM) displayed potent AChE inhibition. These compounds are currently the lead compounds for further studies in our laboratory.     

The effects of two HDR brachytherapy schedules in locally advanced cervical cancer treated with concurrent chemoradiation: a study from Chiang Mai, Thailand

Efficacy of different schedules of HDR brachytherapy in concurrent chemoradiotherapy was evaluated. The study compared the effectiveness of the two HDR brachytherapy schedules which have the same Biological Effective Dose (BED) in locally advanced cervical carcinoma that was treated with concurrent chemoradiotherapy. Included in the study were 377 randomly selected patients with advanced carcinoma of the cervix uteri who were treated during the period 2004-2006. Patients were divided into Group I: 7.2 Gy × 3 fractions and Group II: 6 Gy × 4 fractions. With a median follow-up time of 35 months, local control, disease-free survival and overall survival rates were 80.8%, 63.4%, 98.8% in group I and 86.7%, 63.8%, 97.3% in group II, respectively. There was no statistical significance in terms of local control, disease-free survival, overall survival and complication rates between the two treatment schedules which could be observed. Seven patients in group I developed acute grade 2-4 GI toxicities and two patients in group II. In GU toxicities, there were three patients in group I and three patients in group II who developed grade 2-4 toxicities. In late toxicity, no patient developed grade 3-4 GU toxicities in group I while two patients developed grade 3-4 GU toxicities in group II. In GI toxicities, there were five and six patients in group I and group II, respectively, who developed grade 3-4 severity. Both HDR schedules seem to be safe and effective for the treatment of locally advanced cervical cancer.     

Beta-oxygenated analogues of the 5-HT2A serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane

Activation of 5-HT(2A) serotonin receptors represents a novel approach to lowering intraocular pressure. Because 5-HT(2A) serotonin receptor agonists might also produce undesirable central effects should sufficient quantities enter the brain, attempts were made to identify 5-HT(2) serotonin receptor agonists with reduced propensity to penetrate the blood-brain barrier. 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropan-1-ol (6), an analogue of the 5-HT(2) serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; 1a) bearing a benzylic hydroxyl group, was identified as a candidate structure. Of the four optical isomers of 6, the 1R,2R-isomer (6d; K(i) = 0.5 nM) was found to bind at 5-HT(2A) receptors with an affinity similar to that of R(-)DOB (K(i) = 0.2 nM). Like R(-)DOB, 6d behaved as a partial agonist (efficacy ca. 50%) in a 5-HT(2)-mediated calcium mobilization assay. However, in an in vivo test of central action (i.e., stimulus generalization with rats as subjects), 6d was >15 times less potent than R(-)DOB. O-Methylation of 6d (i.e., 7d; 5-HT(2A) K(i) = 0.3 nM) resulted in an agent that behaved as a full (93% efficacy) agonist. Intraocular administration of 300 microg of 6d and 7d to ocular hypertensive monkeys was shown to reduce intraocular pressure by 20-27%. Given the route of administration (i.e., topical), and concentrations necessary to reduce intraocular pressure, compounds such as 6d should demonstrate minimal central effects at potentially useful therapeutic doses and offer useful leads for further development.