Pharmaceutica acta Helvetiae最新文献

Neuronal nicotinic acetylcholine receptors (nAChRs) are a heterogeneous family of related ion channels that are widely distributed throughout the central and peripheral nervous systems. They all share a common architecture of five subunit proteins that combine at the cell surface to create a ligand-gated cation permeable pore. Significant effort is currently being expended by medicinal chemistry teams to synthesize ligands that exhibit selectivity for central over peripheral nAChR subtypes. Within the CNS, multiple nAChR subtypes are recognized, and the discovery of ligands exhibiting selectivity among these subtypes offers an opportunity for the development of novel therapeutic agents. The α4β2 subtype is one of the most abundant nAChR subtypes within the CNS, and has been the primary focus of high affinity ligand design. Nicotine (1), and more recently, epibatidine (2) have served as structural templates for the design of the majority of active compounds. Although the diversity of nAChR ligands is growing, the structural requirements necessary for high affinity binding with the α4β2 receptor remain poorly understood. The putative pharmacophoric elements common to all potent α4β2 ligands include (1) a basic or quaternized nitrogen atom, and (2) a less basic nitrogen or a carbonyl oxygen that presumably interact with electron rich and electron deficient sites on the receptor, respectively. The family of currently known high affinity analogs consists of a diverse array of azacycles containing a basic amine. Several additional basic amine fragments have been identified, including the pyrrolizidine nucleus (exemplified by 8) and the 2-azabicyclo[2.2.1]heptane skeleton (exemplified by 9). In addition, we have found that the furo[2,3-b]pyridine heterocycle (compound 10) serves as useful bioisosteric replacement for the pyridyl substituent of nicotine. A preliminary pharmacophore model is proposed in which a reasonable superposition of the putative pharmacophoric elements of the diverse array of high affinity ligands for the α4β2 nAChR reported herein may be accommodated.

A brief survey of the history of the development of the concept of the pharmacological receptor is presented. From the pioneering concepts of Paul Ehrlich, John Langley and others, receptors are described in terms of their recognition properties, their structures, transducing abilities and the impact of genomics and their role in contributing to genetic diseases. The receptor concept has firmly underpinned our advances in drug development and molecular medicine of the latter half of this century and it is clear that it will continue to drive pharmaceutical developments in the 21st century.

Despite recent encouraging declines, cardiovascular disease (CVD) is still responsible for about 50% of premature death in the Western industrialized countries, greater than cancer, AIDS and accidents, combined. Different aspects of the disease have been considered and the main currently available and possible future drugs whose effect is based on interaction with a receptor have been reviewed. Catecholamines receptors ligands, mainly β-blockers, and the new angiotensin II antagonists represent the most important classes among the established therapies. Investigational approaches such as the oral glycoprotein GPIIb/IIIa antagonists and endothelin, adenosine and neuropeptide Y receptors ligands are discussed. Receptorology represents just a part of the therapeutical approach to CVD, where other classes of drugs with enzyme or ionic channel based mechanisms are largely used and innovative therapies based on the most advanced research techniques could early become reality.

The identification of new binding sites raises the problem of defining their role, if any. At times they are shown to be pharmacological receptors, in a strict sense, as they fulfill certain requirements, and a precise physiological role and function, and an endogenous ligand (neurotransmitter) are discovered. At other times, however, neither a clear physiological role nor an endogenous ligand are found, but the term “receptor” is still used, although it may not be a proper one in the conventional pharmacological sense. Furthermore, no clear intracellular signalling transduction pathway is defined and, as a consequence, it is not possible to determine whether drugs binding to these receptors act as agonists or antagonists. What their structure and biological function are and how they mediate the pharmacological effects of ligands may remain for a long time an enigma. The matter, in any case, is of great interest to researchers of different areas, especially to medicinal chemists who foresee novel potential targets for therapeutic interventions. In this meeting one section is dedicated to two examples of this kind of receptors: imidazoline (I) and sigma (σ) receptors.

In this chapter we summarize some aspects of the structure-functional relationship of the α1a and α1b-adrenergic receptor subtypes related to the receptor activation process as well as the effect of different alpha-blockers on the constitutive activity of the receptor. Molecular modeling of the α1a and α1b-adrenergic receptor subtypes and computational simulation of receptor dynamics were useful to interpret the experimental findings derived from site directed mutagenesis studies.

Changes in the numbers of human cardiac adrenoceptors (ARs) are associated with various diseases, such as myocardial ischemia, congestive heart failure, cardiomyopathy and hypertension. There is a clear need for capability to assess human cardiac ARs directly in vivo. Positron emission tomography (PET) is an imaging technique that provides this possibility, if effective radioligands can be developed for the targeted ARs. Here, the status of myocardial AR radioligand development for PET is described. Currently, there exist effective radioligands for imaging β-ARs in human myocardium. One of these, [${}^{11}\text{C}$](S)-CGP 12177, is applied extensively to clinical research with PET, sometimes with other tracers of other aspects of the noradrenalin system. Alternative radioligands are in development for β-ARs, including β₁-selective radioligands. A promising radioligand for imaging myocardial α₁-ARs, [${}^{11}\text{C}$]GB67, is now being evaluated in human PET experiments.