Charlotta Mellin

Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone.

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 (125)I-T(3) to the human thyroid hormone receptors (hThR) alpha(1) and beta(1). T(3)-Antagonism was confirmed in reporter cell assays employing CHOK1 cells (Chinese hamster ovary cells) stably transfected with hThR alpha(1) or hThR beta(1) and an alkaline phosphatase reporter gene downstream a thyroid response element. The derived IC(50) values were 2.2 microM for hThR alpha(1) and 4.1 microM for hThR beta(1). 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% (APD(90)) 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.

Chapter 8 Stereoselectivity of nicotinic receptors

Publisher Summary This chapter discusses the stereoselectivity of nicotinic receptors. Acetylcholine, the endogenous transmitter at nicotinic and muscarinic receptors is a flexible and achiral molecule. To determine receptor-bound conformations/pharmacophores chiral and semirigid or rigid derivatives is used. Such compounds have few low-energy conformations and the stereoselectivity that may be obtained is useful when discussing structural requirements for binding to or activation of the receptor. The chapter uses (+)-anatoxin-a and (-)-cytisine—two semirigid and potent nicotinic-receptor agonists—to model nicotinic receptor activity. Isoarecolone methiodide is also included in the model. The model is used to predict the stereoselectivity of a recently reported, potent but racemic bicyclic agonist called pyridol [3,4-b] homotropane (PHT) and to discuss the stereoselectivity of nicotine. The structures of the compounds are presented.

Effects of the C3-methylated derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on central 5-hydroxytryptamine receptors

The effects of the four possible C3-methylated stereoisomers of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) ((-)-CM-11, (+)-CM-11, (-)-CM-12, (+)-CM-12) on brain 5-hydroxytryptamine (5-HT) receptor functions were studied in rats. (-)-CM-11 and (+)-CM-12 inhibited dose dependently in all brain parts the accumulation of 5-hydroxytryptophan following decarboxylase inhibition. Their antipodes were inactive. The disappearance of 5-HT induced by alpha-propyldopacetamide was retarded by (-)-CM-11 and (+)-CM-12. The biochemically active isomers produced a flat body posture and forepaw treading. The results indicate that (-)-CM-11 and (+)-CM-12 stimulate 5-HT receptors directly although not as potently as 8-OH-DPAT. The concentration of dopamine was lowered and that of homovanillic acid was elevated by (+)-CM-11 and by both enantiomers of CM-12 in the corpus striatum and in the limbic system of rats. The accumulation of DOPA following decarboxylase inhibition was not markedly changed by any of the compounds. Locomotor activity was enhanced by (+)-CM-11 but not by any of the other compounds, and the effect was haloperidol-resistant. (+)-CM-11 induced no asymmetry in rats in which the corpus striatum was inactivated on one side. Thus, none of the isomers of CM-11 or CM-12 appears to have any effect on the dopamine receptors.

Stereoselective synthesis of methoxy substituted 1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolines

Abstract The preparation of the cis - and trans -isomers of 6- and 9-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[ g ]-quinoline is reported. The syntheses involved reductions of cyclic iminium chlorides, which afforded the diastereomers conveniently and in good yields. Small cis/trans ratios were obtained with NaCNBH3 as the reducing agent. Catalytic hydrogenation using PtO2 in THF or t -BuOH gave the largest cis/trans ratios. The N-benzyl derivatives were prepared to permit determination of relative stereochemistries.

Modelling of Drug–Receptor Interactions: Stereoselectivity of 5-Hydroxytryptamine and Dopamine Receptors in the Brain

Publisher Summary Neurotransmitters such as dopamine (DA) and serotonin (5-HT) are achiral and fairly flexible molecules that act on a variety of biological targets. DA stimulates D1-receptors and pre- and postsynaptic D2-receptors and 5-HT interacts with at least seven subtypes of 5-HT-receptors. These neurotransmitters are nonselective, that is, they interact also with other neurotransmitter receptors, and drugs with such pharmacological profiles are not useful as therapeutic agents. This chapter discusses that the nonselective actions of the neurotransmitters are not surprising when considering that many of their receptors belong to the G-protein coupled receptor super family. There are considerable amino acid homologies between receptors in this class. The seven putative transmembrane regions, which appear to be common to all G-protein bound receptors and could be responsible for ligand binding, have very similar amino acid sequences. Also, the various receptors appear to transmit the chemical message from the neurotransmitter by similar mechanisms. It is a well-established strategy among medicinal chemists to introduce structural modifications in neurotransmitters in order to obtain drugs with the desired pharmacological selectivity.

Indirect Modelling of Drug-Receptor Interactions

The rapid progress in the area of molecular biology has provided us with the primary structures of a large variety of receptor proteins, many of which belong to the G-protein coupled receptor super family (e.g., dopamine (DA) D1 and D2 receptors, serotonin (5-HT) 5-HT1A, 5-HT1C and 5-HT2 receptors, and muscarinic m1–m5 receptors).1–4These receptor proteins are believed to form seven transmembrane helixes which associate to generate a hydrophilic pore (or groove). The binding site for the ligand is thought to be located within this hydrophilic environment. However, experimental evidence on the 3D-structures of various G-protein coupled receptors is still lacking. Therefore, it is not possible to design ligands for these receptors based on receptor/ligand complementarity. Instead, one has to rely on indirect design methods. These may be based on (a) classical QSAR-techniques, which efficiently describe lipophilic and electronic properties, (b) methods related to the active analogue approach, which in a qualitative sense, takes into account topology and certain other molecular features, and (c) the more recent 3D-QSAR method,5 which may provide quantitative information on the relation between biological activity and steric as well as electronic properties.