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A total of 115 suicide cases dealt with by St. Pancras Coroner's Court, London, UK were studied in order to determine what patterns exist regarding the age and gender of the victims and chosen method of suicide. The results were compared with those of a 1998 study of suicides in England and Wales commissioned by the UK Home Office. It was found that suicides in the male population are approximately twice as common as female victims of suicide. In terms of gross number of cases, the peak age group for both males and females resorting to suicide was found to be the 15-44 age group. When the results were standardised according to 2001 census data, however, the most vulnerable age group per head of population for both sexes was 75 and over. Good agreement was found between the results of this study and those of the Home Office Study.

Endogenous thyroid receptor hormones 3,5,3‘,5‘-tetraiodo-l-thyronine (T4, 1) and 3,5,3‘-triiodo-l-thyronine (T3, 2) exert a significant effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and overall sense of well being. The literature suggests many or most effects of thyroid hormones on the heart, in particular on the heart rate and rhythm, are mediated through the TRα1 isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRβ1 isoform of the receptor. Some effects of thyroid hormones may be therapeutically useful in nonthyroid disorders if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering for treating hyperlipidemia, amelioration of depression, and stimulation of bone formation in osteoporosis. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, cardiovascular toxicity. Consequently, development of thyroid hormone receptor agonists that are selective for the β-isoform could lead to safe therapies for these common disorders while avoiding cardiotoxicity. We describe here the synthesis and evaluation of a series of novel TR ligands, which are selective for TRβ1 over TRα1. These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R1-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors α1 and β1 (TRα1 and TRβ2) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRα1 or hTRβ1 and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFα1 and TRAFβ1). Affinity increases in the order formic, acetic, and propionic acid, while β-selectivity is highest when the R1 position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED15), cholesterol (ED50), and TSH (ED50). Potency for tachycardia was significantly reduced for the TRβ selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold therapeutic window between heart rate and cholesterol, which is consistent with the action of ligands that are approximately 10-fold more selective for TRβ1. We also report the X-ray crystallographic structures of the ligand binding domains of TRα and TRβ in complex with 15. These structures reveal that the single amino acid difference in the ligand binding pocket (Ser277 in TRα or Asn331 in TRβ) results in a slightly different hydrogen bonding pattern that may explain the increased β-selectivity of 15.

Recent developments in antiarrhythmic therapy have indicated that the best approach to pharmacologically controlling supraventricular arrhythmias and life-threatening ventricular tachyarrhythmias is by prolonging cardiac repolarization rather than by blocking conduction. In this context, amiodarone has emerged as the most potent compound, but its universal use has been limited by its toxicity profile. There are data to suggest that an important component of amiodarones antiarrhythmic action might be mediated via inhibition of thyroid hormone action in the heart. Therefore, a new series of carboxymethoxybenzoyl and benzyl derivatives of benzofuran has been prepared and evaluated as thyroid hormone receptor antagonists. Within this series, 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran KB130015 (7) was found to reveal the most promising in vitro data. It inhibits the binding of ¹²⁵I-T3 to the human thyroid hormone receptors (hThR) α1 and β1. T3-Antagonism was confirmed in reporter cell assays employing CHOK1 cells (Chinese hamster ovary cells) stably transfected with hThRα1 or hThRβ1 and an alkaline phosphatase reporter gene downstream a thyroid response element. The derived IC50 values were 2.2 μM for hThRα1 and 4.1 μM for hThRβ1. Compound 7 was selected for further characterization of chronic effects on ventricular papillary muscle by transmembrane electrophysiology after daily intraperitoneal injection of the ligand (40 mg/kg body weight) in guinea pigs. Compound 7 was found to prolong the action potential duration at 90% (APD90) repolarization time (219 ± 22 ms, control:  186 ± 9 ms, p < 0.01) without exhibiting any reverse rate dependency of action in a manner similar to that of amiodarone. In general, preliminary tolerance experiments with 7 demonstrated an improved safety profile compared to that of amiodarone. In summary, 7 appears to be less toxic than amiodarone while maintaining its electrophysiologic properties consistent with antiarrhythmic activity. Its potential antiarrhythmic actions warrant further investigations.

Although many different types of compounds have been tested for 5-hydroxytryptamine1A (5-HT1A) binding affinity, much remains to be learned about the structural requirements associated with 5-HT1A agonism, partial agonism, and antagonism. The present study uses the forskolin-stimulated adenylate cyclase (FSC) assay as a functional screen in rat hippocampal membranes to examine structure-activity relationships for a series of enantiomers of novel analogs of the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The findings illustrate that there can be large enantiomeric differences in intrinsic activity at the 5-HT1A receptor, independent of enantiomeric effects on binding affinity. Generally, for each enantiomeric pair exhibiting stereoselective 5-HT1A binding, the enantiomer with the higher affinity also displayed the greater amount of 5-HT1A intrinsic activity in the FSC assay. Interestingly, the enantiomers of 8-OH-DPAT itself displayed stereoselective differences in intrinsic activity but not 5-HT1A affinity. Several of the compounds, namely (S)-UH-301, (2R,3R)-CM-12, and (1S,2R)-LEA-146, may have potential as prototypes for selective 5-HT1A antagonists, and (S)-UH-301 itself may be useful as a selective 5-HT1A antagonist. The FSC data presented here are in good agreement with reported measures of in vivo 5-HT1A activity, which were in part the basis of a recently proposed model for the 5-HT1A pharmacophore [J. Med. Chem. 34: 497-510 (1991)].

8‐Methoxytetralone (I) is converted to the benzocycloheptenone (IV) via ring expansion of the methylene derivative (III).

The tetralone derivatives (VII) mentioned in the title are prepared by three different methods as shown in the reaction scheme: either starting with the dimethoxy naphthalenes (I) by Birch reduction, cyclopropanation and subsequent hydrolysis or by methylation, reduction and hydrolysis or from the α‐methylindanones (VIII) by Wittig olefination and Tl(NO3)3‐induced ring expansion.