Current Topics in Medicinal Chemistry - Volume 4, Issue 3, 2004

Advances in the understanding of the neurobiology of the nicotinic receptor have started to be matched by an appreciation of the potential role of these receptors in a variety of neuropsychiatric disorders. While alterations in nicotinic receptor number and / or function have been associated with such conditions as Alzheimer's disease for several years, there is increasing evidence that nicotinic receptor function may play a significant role in other disorders as well including schizophrenia, Parkinson's disease, anxiety disorders, and attention deficit-hyperactivity disorder (ADHD). Research in our laboratory and those of other investigators have utilized sophisticated psychopharmacological, cognitive, electrophysiological, neuroimaging and other techniques to assess the impact of nicotinic receptor modulation on the clinical expression of these disorders. This manuscript reviews data, both experimental and clinical, relating to the role of nicotine and / or nicotinic receptor function in a variety of neuropsychiatric disorders with the perspective of developing appropriate targets for therapeutic drug development.

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in the mammalian central nervous system (CNS). Despite this, very little was known, until recently, about their physiological role. In the periphery, nicotinic receptors mediate vital excitatory fast synaptic cholinergic transmission at both the neuromuscular junction and ganglia. In the brain, this role has been mainly “delegated” to glutamate receptors. The very broad cholinergic innervations of most brain areas, including the cortex, have implicated this system, and brain nicotinic receptors in particular, in a unique “modulatory” role of other transmitters systems. Recent evidence confirms, on one hand, that brain nicotinic receptors have a dominant “presynaptic” modulatory function, controlling the release of both acetylcholine (auto-receptors) and other neurotransmitters (hetero-receptors). On the other hand, more experimental data support the idea that a variable component of fast synaptic transmission in the brain can also be mediated by “postynaptic” nicotinic receptors, which, in turn, can control cell excitability. A challenging goal is to identify which one of the plethora of nicotinic receptor subtypes is mediating each effect in different brain areas, and which of these receptors and functions are lost or affected in different human neuro-psychiatric disorders. Needless to say, a better understanding of the physiological role of brain nicotinic receptors will drive our quest for more selective and efficacious nicotinic receptor targeted therapeutic agents.

In the last decade, nicotinic acetylcholine receptors (nAChRs) have emerged as important targets for drug discovery. The therapeutic potential of nicotinic agonists depends substantially on the ability to selectively activate certain receptor subtypes that mediate beneficial effects. The design of such compounds has proceeded in spite of a general shortage of data pertaining to subtype selectivity. Medicinal chemistry efforts have been guided principally by binding affinities to the α4β2 and / or α7 subtypes, even though these are not predictive of agonist activity at either subtype. Nevertheless, a diverse family of nAChR ligands has been developed, and several analogs with promising therapeutic potential have now advanced to human clinical trials. This paper provides an overview of the structure-affinity relationships that continue to drive development of new nAChR ligands.

Neuronal nicotinic acetylcholine ion channel receptors (nAChRs) exist as several subtypes and are involved in a variety of functions and disorders of the central nervous system (CNS), such as Alzheimer's and Parkinson's diseases. The lack of reliable information on the 3D structure of nAChRs prompted us to focus efforts on pharmacophore and structure-affinity relationships (SAFIRs). The use of DISCO (DIStance COmparison) and Catalyst / HipHop led to the formulation of a pharmacophore that is made of three geometrically unrelated features: (i) an ammonium head involved in coulombic and / or H-bond interactions, (ii) a lone pair of a pyridine nitrogen or a carbonyl oxygen, as H-bond acceptor site, and (iii) a hydrophobic molecular region generally constituted by aliphatic cycles. The quantitative SAFIR (QSAFIR) study was carried out on about three hundred nicotinoid agonists, and coherent results were obtained from classical Hansch-type approach, 3D QSAFIRs, based on Comparative Molecular Field Analysis (CoMFA), and trade-off models generated by Multi-objective Genetic QSAR (MoQSAR), a novel evolutionary software that makes use of Genetic Programming (GP) and multi-objective optimization (MO). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the major factors modulating the receptor affinity, whereas CoMFA allowed us to merge progressively single-class models in a more global one, whose robustness was supported by crossvalidation, high prediction statistics and satisfactory predictions of the affinity data of a true external ligand set (r2 pred = 0.796). Next, MoQSAR was used to analyze a data set of 58 highly active nicotinoids characterized by 56 descriptors, that are log P, MR and 54 low inter-correlated WHIM (Weighted Holistic Invariant Molecular) indices. Equivalent QSAFIR models, that represent different compromises between structural model complexity, fitting and internal model complexity, were found. Our attention was mostly engaged by a number of nonlinear QSAFIRs, which relate nAChR affinity with the log P and directional WHIM descriptors. The results reviewed herein show as QSAFIRs may helpfully complement the pharmacophores, thus enhancing the applicability of computer-aided methodologies in the field of nAChR agonists.

Simple determination of KA or KD values makes it possible to calculate the standard free energy DG° = - RTlnKA = RT lnKD (T= 298.15 K) of the binding equilibrium but not that of its two components as defined by the Gibbs equation DG° = DH° - TDS° where DH° and DS° are the equilibrium standard enthalpy and entropy, respectively. Recently, it has been shown that the relative DH° and DS° magnitudes can often give a simple “in vitro” way for discriminating “the effect”, that is the manner in which the drug interferes with the signal transduction pathways. This particular effect, called “thermodynamic discrimination”, results from the fact that binding of antagonists may be enthalpy-driven and that of agonists entropy-driven, or vice-versa. In the past, the thermodynamic discrimination was reported for the β-adrenergic G-protein-coupled receptor (GPCR) and confirmed later for adenosine A1, A2A and A3 receptors. Moreover, it has been found that the binding of all ligand-gated ion-channel receptors (LGICR) investigated was thermodynamically discriminated. In particular, affinity constants for typical neuronal nicotinic receptor ligands were obtained by both saturation and inhibition experiments with the radioligand [3H]-cytisine, a ganglionic nicotinic agonist. Thermodynamic parameters indicated that agonistic binding was both enthalpy- and entropy-driven, while antagonistic binding was totally entropy-driven. These results have shown that neuronal nicotinic receptor agonists and antagonists were thermodynamically discriminated. On these grounds, the thermodynamic behaviour makes it possible to discriminate drug pharmacological profiles in vivo through binding experiments in vitro.

Current analgesics, such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), are largely refinements of approaches available for more than 100 years and have critical liabilities and limitations. A number of new molecular targets for analgesia have been proposed in recent years, including the neuronal nicotinic acetylcholine receptor (nAChR). Agonists at neuronal nAChRs have antinociceptive effects in a variety of preclinical pain models. Moreover, nicotine can decrease experimentally-induced pain in humans without disrupting normal tactile sensation. These data from both experimental animals and humans suggest that compounds targeting neuronal nAChRs may represent a new class of analgesic agents. In this paper, we provide brief overviews of the physiology of pain, the animal models used to assess potential analgesics preclinically, and the biology of nAChRs. We then provide a review of preclinical data on the antinociceptive effects of a variety of neuronal nAChR agonists and a discussion of potential mechanisms, including evidence that antinociception is mediated by activation of brainstem nuclei with descending inhibitory inputs to the spinal cord. An evaluation of the clinical potential of this approach must also consider potential side effects. Undesirable side effects of nicotine are well known, but as we will discuss in detail, these effects are not produced by all neuronal nAChR agonists and the existence of neuronal nAChR subtypes may provide a basis for separating therapeutic effects from toxicities.