Δ9-Tetrahydrocannabinol (THC): A Critical Overview of Recent Clinical Trials and Suggested Guidelines for Future Research.

In this overview, we seek to appraise recent experimental and observational studies investigating THC and its potential role as adjunctive therapy in various medical illnesses. Recent clinical trials are suggestive of the diverse pharmacologic potentials for THC but suffer from small sample sizes, short study duration, failure to address tolerance, little dose variation, ill-defined outcome measures, and failure to identify and/or evaluate confounds, all of which may constitute significant threats to the validity of most trials. However, the existing work underscores the potential therapeutic value of THC and, at the same time, calls attention to the critical need for better-designed protocols to fully explore and demonstrate safety and efficacy. In the most general sense, the present brief review illuminates some intriguing findings about THC, along with the basic threats to the validity of the research that supports those findings. The intent is to highlight existing generic weaknesses in the existing randomized controlled trial literature and, most importantly, provide guidance for improved clinical research.

Novel α7 nicotinic acetylcholine receptor modulators as potential antitussive agents.

A novel series of α7 nicotinic acetylcholine receptor (nAChR) modulators was designed and evaluated for antitussive activity in an in vivo guinea pig model of chemically induced cough. Compound 16 at all tested doses (9.5, 3 and 1 mg/kg) significantly (p < 0.01) reduced the cumulative number of coughs and showed similar results to a positive control (codeine at 30 mg/kg). Among three different administration routes (intraperitoneal, oral and inhalation), compound 16 exerted a significant antitussive effect in guinea pigs at an inhaled dose as low as 0.4 mg/kg (p < 0.05). α7 nAChR modulators may provide a novel, non-narcotic approach to therapy in patients with acute and chronic cough.

Application of Secondary Electrospray Ionization Coupled with High-Resolution Mass Spectrometry in Chemical Characterization of Thermally Generated Aerosols.

Inhalation as a route for administering drugs and dietary supplements has garnered significant attention over the past decade. We performed real-time analyses of aerosols using secondary electrospray ionization (SESI) technology interfaced with high-resolution mass spectrometry (HRMS), primarily developed for exhaled breath analysis with the goal to detect the main aerosol constituents. Several commercially available inhalation devices containing caffeine, melatonin, cannabidiol, and vitamin B12 were tested. Chemical characterization of the aerosols produced by these devices enabled detection of the main constituents and screening for potential contaminants, byproducts, and impurities in the aerosol. In addition, a programmable syringe pump was connected to the SESI-HRMS system to monitor aerosolized active pharmaceutical ingredients (APIs) such as chloroquine, hydroxychloroquine, and azithromycin. This setup allowed us to detect caffeine, melatonin, hydroxychloroquine, chloroquine, and cannabidiol in the produced aerosols. Azithromycin and vitamin B12 in the aerosols could not be detected; however, our instrument setup enabled the detection of vitamin B12 breakdown products that were generated during the aerosolization process. Positive control was realized by liquid chromatography-HRMS analyses. The compounds detected in the aerosol were confirmed by exact mass measurements of the protonated and/or deprotonated species, as well as their respective collision-induced dissociation tandem mass spectra. These results reveal the potential wide application of this technology for the real-time monitoring of aerosolized active pharmaceutical ingredients that can be administered through the inhalation route.

Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions.

In vitro screening for pharmacological activity of existing drugs showed chloroquine and hydroxychloroquine to be effective against severe acute respiratory syndrome coronavirus 2. Oral administration of these compounds to obtain desired pulmonary exposures resulted in dose-limiting systemic toxicity in humans. However, pulmonary drug delivery enables direct and rapid administration to obtain higher local tissue concentrations in target tissue. In this work, inhalable formulations for thermal aerosolization of chloroquine and hydroxychloroquine were developed, and their physicochemical properties were characterized. Thermal aerosolization of 40 mg/mL chloroquine and 100 mg/mL hydroxychloroquine formulations delivered respirable aerosol particle sizes with 0.15 and 0.33 mg per 55 mL puff, respectively. In vitro toxicity was evaluated by exposing primary human bronchial epithelial cells to aerosol generated from Vitrocell. An in vitro exposure to 7.24 µg of chloroquine or 7.99 µg hydroxychloroquine showed no significant changes in cilia beating, transepithelial electrical resistance, and cell viability. The pharmacokinetics of inhaled aerosols was predicted by developing a physiologically based pharmacokinetic model that included a detailed species-specific respiratory tract physiology and lysosomal trapping. Based on the model predictions, inhaling emitted doses comprising 1.5 mg of chloroquine or 3.3 mg hydroxychloroquine three times a day may yield therapeutically effective concentrations in the lung. Inhalation of higher doses further increased effective concentrations in the lung while maintaining lower systemic concentrations. Given the theoretically favorable risk/benefit ratio, the clinical significance for pulmonary delivery of aerosolized chloroquine and hydroxychloroquine to treat COVID-19 needs to be established in rigorous safety and efficacy studies. Graphical abstract.

An electrophysiological characterization of naturally occurring tobacco alkaloids and their action on human α4ß2 and α7 nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptor (nAChR) subtype-selective pharmacological profiles of tobacco alkaloids are essential for understanding the physiological effects of tobacco products. In this study, automated electrophysiology was used to functionally characterize the effects of distinct groups of tobacco alkaloids on human α4ß2 and α7 nAChRs. We found that, in tobacco alkaloids, pyridine as a hydrogen bond acceptor and a basic nitrogen atom at a distance of 4-7 Šare pharmacophoric elements necessary for molecular recognition by α4ß2 and α7 nAChRs with various degrees of selectivity, potency, and efficacy. While four alkaloids-nicotine, nornicotine, anabasine and R-anatabine-potently activated α4ß2, they were also weak agonists of α7 nAChRs. Nicotine was the most potent agonist of α4ß2, while anabasine elicited the highest activation of α7. None of the tobacco alkaloids enhanced nAChR activity elicited by the endogenous ligand acetylcholine; therefore, none was considered to be a positive allosteric modulator (PAM) of either α4ß2 or α7 nAChRs. In contrast, we identified tobacco alkaloids, such as the tryptophan metabolite 6-hydroxykynurenic acid, that decreased the activity of both α4ß2 and α7 nAChRs. Our study identified a class of alkaloids with positive and negative effects against human α4ß2 and α7 nAChRs. It also revealed human α4ß2 to be the principal receptor for sensing the most abundant alkaloids in tobacco leaves.

Antiparasitic properties of leaf extracts derived from selected Nicotiana species and Nicotiana tabacum varieties.

Within the traditional pharmacopeia, tobacco (Nicotiana spp.) is often cited as an efficient pesticide. This activity is generally attributed to nicotine, but tobacco plants contain other alkaloids that could potentially contribute to this effect. In this study, we tested methanolic extracts of N. glutinosa, N. glauca, N. debneyi, and N. tabacum (putrescine N-methyltransferase line, burley TN90 and Stella, Virginia ITB 683 and K326), selected according to alkaloid content. Their antiparasitic activity was evaluated in bioassays against adult fleas (Ctenocephalides felis), blowfly (Lucilia cuprina) larvae, nematodes (Caenorhabditis elegans), and ticks (Rhipicephalus sanguineus larvae and adults, Ixodes ricinus nymphs). None of the extracts killed fleas and blowfly larvae effectively at the concentrations tested. Only N. tabacum K326 and N. glutinosa exhibited moderate anthelmintic activity. All extracts significantly repelled R. sanguineus ticks, but not I. ricinus, and the nicotine-rich extracts rapidly knocked down all tick species and stages at high concentrations. The link between nicotine and tick knockdown was confirmed by successfully testing the pure alkaloid at concentrations found in the tobacco extracts. In contrast, repellent activity could not be correlated to the individually tested alkaloids (nicotine, nornicotine, anabasine, anatabine), although anatabine and nornicotine were active in the tick bioassay at high concentrations.

Identification and pharmacological characterization of 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides as novel ligands for the α4ß2 and α6/α3ß2ß3 nicotinic acetylcholine receptors (nAChRs).

We have synthesized a novel series of compounds, 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides, targeting both the α4ß2 and α6/α3ß2ß3 nAChRs. Members of the obtained chemical library are partial or full agonists at both the high sensitivity (α4)2(ß2)3 and α6/α3ß2ß3 nAChRs. 3-(Cyclopropylcarbonyl)-3,6-diazabicyclo[3.1.1]heptane (TC-8831 or compound 7 herein) demonstrated a safe in vitro pharmacological profile and the potential for reducing or preventing L-dopa-induced dyskinesias (LID) in several in vivo animal models [1-4]. In vivo metabolism studies in rat and in vitro metabolism studies in liver microsomes from human, rat, dog and monkey showed TC-8831 to be relatively stable. In vivo pharmacokinetic analysis in the rat confirmed brain penetration, with an average brain:plasma ratio of approximately 0.3 across time points from 0.5 to 4 h. Docking into homology models predicted alternative binding modes for TC-8831 and highlighted the importance of the cationic center, hydrogen-bond acceptor, and hydrophobic aliphatic features in promoting binding affinity to both nAChRs. Pharmacophore elucidation confirmed the importance of these key interactions. QSAR modeling suggested that binding affinity is primarily driven by ligand shape, relative positive charge distribution onto the molecular surface, and molecular flexibility. Of the two subtypes, ligand binding to α6ß2ß3 appears to be more sensitive to bulkiness and flexibility.

Computational studies of novel carbonyl-containing diazabicyclic ligands interacting with α4ß2 nicotinic acetylcholine receptor (nAChR) reveal alternative binding modes.

We have carried out computational studies on interactions of diazabicyclic amide analogs with α4ß2 nAChR using homology modeling, docking and pharmacophore elucidation techniques. We have found alternative ligand binding modes in most cases. All these diverse poses exhibit the quintessential hydrogen-bonding interaction between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the highly conserved Trp-149. This hydrogen bond was always found to be shorter than the one contracted by the ligand carbonyl group and a second hydrogen-bond made by the cationic center with Tyr-93 of the principal face of the protein. In most of the poses observed, cation-π interactions involved three aromatic residues located in the principal face of the protein: Trp-149, Tyr-190 and Tyr-197. The latter amino acid residue appears to often donate a hydrogen-bond to the ligand carbonyl oxygen atom. We also describe two rings of alternative receptor-based hydrogen-bond donor features equidistantly separated from the carbonyl oxygen of the highly conserved Trp-149 approximately by 5 and 8Å, respectively. These findings could be exploited to design diverse and selective novel chemical libraries for the treatment of diseases and conditions where the α4ß2 nAChR is disrupted, such as Alzheimer disease, Parkinson's disease and l-dopa-induced dyskinesia (LID).

Novel nicotinic acetylcholine receptor agonists containing carbonyl moiety as a hydrogen bond acceptor.

A novel series of α4ß2 nAChR agonists lacking common pyridine or its bioisosteric heterocycle have been disclosed. Essential pharmacophoric elements of the series are exocyclic carbonyl moiety as a hydrogen bond acceptor and secondary amino group within diaza- or azabicyclic scaffold. Computer modeling studies suggested that molecular shape of the ligand also contributes to promotion of agonism. Proof of concept for improving working memory performance in a novel object recognition task has been demonstrated on a representative of the series, 3-propionyl-3,7-diazabicyclo[3.3.0]octane (34).

3D molecular descriptors important for clinical success.

The pharmacokinetic and safety profiles of clinical drug candidates are greatly influenced by their requisite physicochemical properties. In particular, it has been shown that 2D molecular descriptors such as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers correlate with clinical success. Using the proteomic off-target hit rate of nicotinic ligands, we found that shape-based 3D descriptors such as the radius of gyration and shadow indices discriminate off-target promiscuity better than do Fsp3 and the number of stereo centers. We have deduced the relevant descriptor values required for a ligand to be nonpromiscuous. Investigating the MDL Drug Data Report (MDDR) database as compounds move from the preclinical stage toward the market, we have found that these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD. Further, these computed 3D molecular descriptors correlate well with experimentally observed solubility, which is among well-known physicochemical properties that drive clinical success. We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria. Our studies suggest that spherical compounds (rather than their elongated counterparts) with a minimal number of aromatic rings may exhibit a high propensity to advance from clinical trials to market.

Discovery of (2S,3R)-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]furan-2-carboxamide (TC-5619), a selective α7 nicotinic acetylcholine receptor agonist, for the treatment of cognitive disorders.

(2S,3R)-N-[2-(Pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]furan-2-carboxamide (7a, TC-5619), a novel selective agonist of the α7 neuronal nicotinic acetylcholine receptor, has been identified as a promising drug candidate for the treatment of cognitive impairment associated with neurological disorders. 7a demonstrated more than a thousand-fold separation between the affinities for the α7 and α4ß2 receptor subtypes and had no detectable effects on muscle or ganglionic nicotinic receptor subtypes, indicating a marked selectivity for the central nervous system over the peripheral nervous system. Results obtained from homology modeling and docking explain the observed selectivity. 7a had positive effects across cognitive, positive, and negative symptoms of schizophrenia in animal models and was additive or synergistic with the antipsychotic clozapine. Compound 7a, as an augmentation therapy to the standard treatment with antipsychotics, demonstrated encouraging results on measures of negative symptoms and cognitive dysfunction in schizophrenia and was well tolerated in a phase II clinical proof of concept trial in patients with schizophrenia.

Analgesic effects mediated by neuronal nicotinic acetylcholine receptor agonists: correlation with desensitization of α4ß2* receptors.

Nicotinic α4ß2* agonists are known to be effective in a variety of preclinical pain models, but the underlying mechanisms of analgesic action are not well-understood. In the present study, we characterized activation and desensitization properties for a set of seventeen novel α4ß2*-selective agonists that display druggable physical and pharmacokinetic attributes, and correlated the in vitro pharmacology results to efficacies observed in a mouse formalin model of analgesia. ABT-894 and Sazetidine-A, two compounds known to be effective in the formalin assay, were included for comparison. The set of compounds displayed a range of activities at human (α4ß2)(2)ß2 (HS-α4ß2), (α4ß2)(2)α5 (α4ß2α5) and (α4ß2)(2)α4 (LS-α4ß2) receptors. We report the novel finding that desensitization of α4ß2* receptors may drive part of the antinociceptive outcome. Our molecular modeling approaches revealed that when receptor desensitization rather than activation activitiesat α4ß2* receptors are considered, there is a better correlation between analgesia scores and combined in vitro properties. Our results suggest that although all three α4ß2 subtypes assessed are involved, it is desensitization of α4ß2α5 receptors that plays a more prominent role in the antinociceptive action of nicotinic compounds. For modulation of Phase I responses, correlations are significantly improved from an r(2) value of 0.53 to 0.67 and 0.66 when HS- and LS-α4ß2 DC(50) values are considered, respectively. More profoundly, considering the DC(50) at α4ß2α5 takes the r(2) from 0.53 to 0.70. For Phase II analgesia scores, adding HS- or LS-α4ß2 desensitization potencies did not improve the correlations significantly. Considering the α4ß2α5 DC(50) value significantly increased the r(2) from 0.70 to 0.79 for Phase II, and strongly suggested a more prominent role for α4ß2α5 nAChRs in the modulation of pain in the formalin assay. The present studies demonstrate that compounds which are more potent at desensitization of α4ß2* receptors display better analgesia scores in the formalin test. Consideration of desensitization propertiesat α4ß2* receptors, especially at α4ß2α5, in multiple linear regression analyses significantly improves correlations with efficacies of analgesia. Thus, α4ß2* nicotinic acetylcholine receptor desensitization may contribute to efficacy in the mediation of pain, and represent a mechanism for analgesic effects mediated by nicotinic agonists.

Multiple interaction regions in the orthosteric ligand binding domain of the α7 neuronal nicotinic acetylcholine receptor.

Neuronal nicotinic receptors (nAChRs) belong to the Cys-loop family of ligand-gated ion channels and are formed from five subunits either as homologous or heterologous, oligomeric receptors, and are of interest as targets for treatment of a variety of central and peripheral nervous system disorders. Using a model of the homopentameric α7 nAChR extracellular region derived from the homologous acetylcholine binding protein (AChBP) from Aplysia California, binding modes of structurally diverse, high affinity α7 ligands were examined by docking to the orthosteric ligand binding domain. While all α7 ligands show similar interactions between the essential positively charged cationic center of the ligand and αTRP147 of the receptor (i.e., hydrogen bond to the tryptophan backbone carbonyl and cation-π interaction), docked poses of various ligands show the potential to interact with three additional regions within the binding domain, identified as regions 1, 2, and 3. Region 1 is located in the vicinity of Loop-E, involves ligand-protein interactions via a network of water-mediated hydrogen bonds, and is analogous to the region where pyridinyl groups are located in many of the AChBP-nicotinic ligand cocrystal structures. Ligands interacting with region 2 probe an area that spans from Loop-E to Loops-D and -F and may contribute to α7-selectivity over other nAChR subtypes. Several high affinity α7 ligands show strong interactions in this region. Region 3 is located near Loop-F of the protein and is analogous to an area involved in binding of an active metabolite derived from DMXBA, in an AChBP cocrystal structure. It appears that π-π interactions contribute to binding affinities of α7 nAChR ligands in this latter region, and further, this region may also contribute to α7-selectivity over other nAChR subtypes. Analysis of the resulting poses suggests that compounds with high α7 binding affinity do not require interactions across all regions simultaneously, but that interactions in multiple regions may enhance ligand binding and increase selectivity. Our results provide insight for further development of selective α7 nAChR ligands and may prove useful for the design of novel scaffolds for specific nicotinic therapeutic agents.

Discovery of 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a novel highly selective α4ß2 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders.

Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent α4ß2 nAChR selective agonists comprising a series of N-acyldiazabicycles. Core characteristics of the series are an exocyclic carbonyl moiety as a hydrogen bond acceptor and endocyclic secondary amino group. These features are positioned at optimal distance and with optimal relative spatial orientation to provide near optimal interactions with the receptor. A novel potent and highly selective α4ß2 nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (56, TC-6683, AZD1446) with favorable pharmaceutical properties and in vivo efficacy in animal models has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions and is currently being progressed to phase 2 clinical trials as a treatment for Alzheimer's disease.

Discovery of novel α7 nicotinic acetylcholine receptor ligands via pharmacophoric and docking studies of benzylidene anabaseine analogs.

Based on pharmacophore elucidation and docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR, novel spirodiazepine and spiroimidazoline quinuclidine series have been designed. Binding studies revealed that some of hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype in comparison with most potent metabolite of GTS-21, 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine. Hydrophobicity and rigidity of the ligand also contribute into its binding affinity. We also describe alternative pharmacophoric features equidistant from the carbonyl oxygen atom of the conserved Trp-148 of the principal face, which may be exploited to further design diverse focused libraries targeting the α7 nAChR.

Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): application to the design of related α7 selective ligands.

AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the α7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH(2) functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-π interactions. The use of AChBPs structure as a surrogate to predict binding affinity to α7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a α7 homology model, Bt or Ac crystal structure is used.

An alpha7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes.

Type 2 diabetes has become a pervasive public health problem. The etiology of the disease has not been fully defined but appears to involve abnormalities in peripheral and central nervous system pathways, as well as prominent inflammatory components. Because nicotinic acetylcholine receptors (nAChRs) are known to interact with anti-inflammatory pathways and have been implicated in control of appetite and body weight, as well as lipid and energy metabolism, we examined their role in modulating biological parameters associated with the disease. In a model of type 2 diabetes, the homozygous leptin-resistant db/db obese mouse, we measured the effects of a novel alpha7 nAChR-selective agonist [5-methyl-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide (TC-7020)] on body mass, glucose and lipid metabolism, and proinflammatory cytokines. Oral administration of TC-7020 reduced weight gain and food intake, reduced elevated glucose and glycated hemoglobin levels, and lowered elevated plasma levels of triglycerides and the proinflammatory cytokine tumor necrosis factor-alpha. These changes were reversed by the alpha7-selective antagonist methyllycaconitine, confirming the involvement of alpha7 nAChRs. Prevention of weight gain, decreased food intake, and normalization of glucose levels were also blocked by the Janus kinase 2 (JAK2) inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490), suggesting that these effects involve linkage of alpha7 nAChRs to the JAK2-signal transducer and activator of transcription 3 signaling pathway. The results show that alpha7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment.

Selective alpha7 nicotinic acetylcholine receptor ligands.

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand gated ion channels of broad distribution and structural heterogeneity. Their functional diversity demonstrated involvement in a variety of neuronal processes (e.g., sensory gating and cognitive function) and generated great interest in them as targets for therapeutic intervention in a number of neuropathological conditions and diseases. In order to control distinct nicotinic functions pharmacologically, it is important to design ligands that selectively interact with distinct receptor subtypes in such a way as to maximize the therapeutic effect and minimize the adverse effects. The alpha7 nAChR, a CNS subtype, has been the most intensively studied nAChR in recent years. Selective alpha7 nAChR agonists have been developed as potential candidates for the treatment of schizophrenia, cognitive disorders (including Alzheimer's disease), and inflammation. Despite early concerns that the rapid desensitization property of the alpha7 nAChR would limit their therapeutic potential, several have already been advanced to clinical trials (e.g., PH-399733, Pfizer; MEM 3454, Memory Pharmaceuticals/Roche). Further development of allosteric modulators and pharmaceutically relevant antagonists might expand the therapeutic potential of compounds that target alpha7 nAChRs. In this review we briefly describe the structure and function of the alpha7 nAChR and its in vitro and in vivo pharmacology, discuss the clinical relevance of these efforts, and review the current progress in alpha7 ligand development.

2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands.

A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha7 over other nAChRs (e.g., the alpha4beta2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-8l), has potent agonistic activity for the alpha7 nAChR (EC(50)=33nM, I(max)=1.0), at concentrations below those that result in desensitization.