Designing a Clinical Education Tracking System: An Innovative Approach.

In clinical education, there is a need for constant evaluation, assessment, and at times immediate feedback for students to recognize areas of success, learning, and areas for improvement. The clinical educator is expected to manage the number of student evaluations and assess their performance, regularly, as needed, and over time. This allows appropriate and timely formative, as well as summative feedback to students and the program. Clinical programs face challenges in finding innovative and efficient methods to track and manage this large volume of seemingly disparate needed and required data. Traditional solutions entail paper-based systems or a paid proprietary clinical tracking system. However, both of these options have their own unique challenges. This perspective article proposes an innovative approach of collecting data electronically via online forms, processing and storing data in cloud-based databases and providing appropriate visualizations for the end users (i.e., students and educators) to analyze and assess the information. Migrating data to be collected in this manner allows for the integration of business intelligence (BI) techniques that provide data mining and machine learning in various user needed methods. This article presents a perspective and an innovative guide for clinical educators on how to develop and design a system that leads to positive sentiments and immediate student feedback regarding their progress to improve student outcomes.

Improved water absorption behaviour of experimental hydrophilic vinyl polysiloxane (VPS) impression materials incorporating a crosslinking agent and a novel surfactant.

OBJECTIVES: To study the effects of incorporating a further crosslinking agent and a novel surfactant on the water absorption behaviour of experimental VPS impression materials. METHODS: Part 1: The water uptake behaviour of Aquasil-Ultra-Monophase (AqM) was studied gravimetrically in three media (DW, 1%NaOCl and Perform ID), at 23 °C and 37 °C, over a period of one and four-months (n = 5) to gain information on long-term immersion. Part 2: Five experimental materials were formulated: Exp-I and II as hydrophobic and Exp-III-V as hydrophilic, containing an additional cross-linking agent (TFDMSOS) and Rhodasurf CET-2 surfactant. Their water uptake and desorption (both at 23 °C) properties (gravemetrically), solubility, pH and diffusion coefficient (DC) data were compared with three commercial, hydrophilic VPS impression materials, over seven days (n = 5). The results were analysed statistically. RESULTS: Part 1: Significant differences in water absorbed by AqM were observed in the three media at 23 °C. Aq M had a significantly higher uptake in 2% Perform ID, than in DW and NaOCl. At 37 °C, over four-months the uptake profiles were more enhanced and differed. Part 2: All Exp and commercial materials significantly increased in weight in both media (DW and 1% NaOCl at 23 °C), with differing uptake profiles and non-reached equilibrium. Exp-VPS absorbed significantly less water than commercial-VPS. Desorption of all VPS from both parts was faster than absorption, followed Fickian diffusion kinetics and reached equilibrium within 1-3 days. Desorption DCs for Exp-VPS were higher than commercial materials (10-10 versus 10-11 m2 s-1). The solubility was higher in 1% NaOCl compared to DW. The pH of DW after immersion of samples significantly increased compared to 1% NaOCl. SIGNIFICANCE: The incorporation of novel cross-linking agent, TFDMSOS and non-ionic surfactant, Rhodasurf CET-2, (ethoxylated-cetyl-oleyl alcohol) improved the dimensional stability of hydrophilic Exp-VPS in DW and 1% NaOCl. These materials merit further research in producing accurate casts of the patient's anatomy following disinfection.

The effects of cross-linking agent and surfactant on the tear strength of novel vinyl polysiloxane impression materials.

OBJECTIVES: To formulate experimental hydrophobic and hydrophilic vinyl polysiloxane (VPS) impression materials ab initio, comprising a novel cross-linking agent, tetra-functional (dimethylsilyl) orthosilicate (TFDMSOS), and a non-ionic surfactant, Rhodasurf CET-2 (ethoxylatedcetyl-oleyl alcohol), and to investigate their effects on tear strength (TS). METHODS: Five experimental formulations (Exp I-V) were prepared and compared with three medium bodied commercial VPS impression materials (Aq M, Elt M, Extr M). Tear test was performed on trouser test specimens (n=12 per material), at four time points (immediately, 24, 72 and 168 hours after setting). FTIR spectroscopy was used for identifying functional bonds and cross-linking. The results were analysed with one-way ANOVA, two-way ANOVA and post hoc Tukey's test using the SPSS PASW statistical 22 software. RESULTS: The material with novel cross-linking agent (Exp II) had significantly higher TSs at all-time points compared to Exp I (control; p˂0.05). Materials incorporating both TFDMSOS and surfactant (Exp III, IV and V), had further significantly increased TS at all-time points, which were concentration dependent. Extr M had a significantly lower TS (immediately after setting and at 24 hours) compared to all Exp and other commercial materials, with the exception of Elt M (difference not significant). The TSs of Exp II-V, after 72 and 168 hours, were significantly higher for than all commercial products and Exp I. FTIR spectra showed the consumption of Si-H groups indicating crosslinking had taken place with the addition of TFDMSOS and surfactant which contributed to an increase in the TS. SIGNIFICANCE: TFDMSOS cross-linking agent increased the TS of Exp II significantly at all-time points compared to the control. Novel surfactant further significantly increased TS, and it was also concentration dependent. Exp VPS with improved TS have been developed, addressing one of the drawbacks of commercial VPS materials.

Experimental hydrophilic vinyl polysiloxane (VPS) impression materials incorporating a novel surfactant compared with commercial VPS.

OBJECTIVES: To formulate experimental hydrophilic (Exp) VPS impression materials incorporating a novel surfactant (Rhodasurf CET-2), and to compare their contact angles (CAs) with commercial materials, before/after disinfection. METHODS: CAs were measured immediately after setting and after disinfection (1% NaOCl; 30min and 24h), together with their change whilst a droplet remained on the materials surface (over 10, 20, 30 60 and 120s), on three commercial (Aquasil Ultra-Monophase [Aq M], Elite HD-Monophase [Elt M], Extrude Medium-bodied [Extr M]) and four experimental (Exp I-IV) materials, using the Drop Shape Analysis 100 technique. The results were compared statistically. RESULTS: CAs of all experimental materials were within the range of those obtained for the commercial materials, with the exception of Exp-IV, which presented with the lowest CAs at the three time points. The control Exp-I was hydrophobic at all three time points (CAs ∼100+), as was Elite. Immediately after setting, Aq M had low CAs but these increased significantly after 30min of disinfection. After twenty four hours' disinfection CAs of all Exp/commercial VPS increased significantly compared to immediately after setting. The CAs of droplets left on the material (120s) decreased with time, even after disinfection, except for Exp-I. SIGNIFICANCE: The novel surfactant Rhodasurf CET-2 in Exp-III and IV, is an effective surfactant, retaining a low CA after disinfection, compared with Igepal CO-530 in Aq M. Disinfecting VPS impression materials for more than 30min increases their surface CAs, and therefore prolonged disinfection periods should be avoided.

A study to investigate and compare the physicomechanical properties of experimental and commercial temporary crown and bridge materials.

OBJECTIVES: To develop two experimental temporary crown and bridge materials with improved physicomechanical properties. METHODS: Commercial materials: Trim (TR, monomethacrylate, Bosworth) and Quicktemp2 (QT, dimethacrylate, Schottlander). EXPERIMENTAL MATERIALS: isobutyl methacrylate/poly(ethyl methacrylate) (IBMA/PEM) and n-butyl methacrylate/PEM (nBMA/PEM), both monomethacrylates. For water absorption/desorption studies rectangular samples (40 mm × 10 mm × 1 mm) of each material were prepared, immersed in deionized water (DW, control) and artificial saliva (AS), and weighed at regular time intervals. %solubility and diffusion coefficients (D) for uptake/loss processes were calculated and compared with theoretical predictions. Polymerization exotherm (cylindrical samples 10 mm × 18 mm) and flexural moduli were measured (three point bending; rectangular samples 80 mm × 10 mm × 4 mm, dry and after 9 days storage in DW). The data were compared statistically. RESULTS: QT and nBMA/PEM had lower %equilibrium uptakes/loss in DW (0.68%/0.884% and 0.64%/0.895% respectively). QT had the lowest water absorption/desorption D (P<0.05) compared to the three monomethacrylates, in DW and AS. %solubility for all systems showed no differences in DW (P>0.05), but a difference for QT in AS (P<0.05). QT reached its maximum temperature rapidly (∼2 min; 3 monomethacrylates ∼7-13 min). The commercial materials exhibited high peak temperatures (∼51°C, P<0.05; experimental materials ∼43°C). QT had a higher flexural modulus (∼4 GPa; 3 monomethacrylates ∼0.7-1 GPa) for dry and wet samples. The moduli for commercial materials reduced significantly after immersion in DW; there was no difference between the dry and wet experimental materials samples (P>0.05). SIGNIFICANCE: The experimental materials merit further studies since they presented with lower setting exotherms, and contained no phthalate plasticizer, thus being less of a risk to patients.

Modification of pH Conferring Virucidal Activity on Dental Alginates.

To formulate an alginate dental impression material with virucidal properties, experimental alginate dental impression materials were developed and the formulations adjusted in order to study the effect on pH profiles during setting. Commercially available materials served as a comparison. Eight experimental materials were tested for antiviral activity against Herpes Simplex Virus type 1 (HSV-1). Changing the amount of magnesium oxide (MgO) used in the experimental formulations had a marked effect on pH. Increasing MgO concentration corresponded with increased pH values. All experimental materials brought about viral log reductions ranging between 0.5 and 4.0 over a period of 4 h. The material with the lowest pH was the most effective. The current work highlights the very important role of MgO in controlling pH profiles. This knowledge has been applied to the formulation of experimental alginates; where materials with pH values of approximately 4.2-4.4 are able to achieve a significant log reduction when assayed against HSV-1.

A novel fluorine-18 ß-fluoroethoxy organophosphate positron emission tomography imaging tracer targeted to central nervous system acetylcholinesterase.

Radiosynthesis of a fluorine-18 labeled organophosphate (OP) inhibitor of acetylcholinesterase (AChE) and subsequent positron emission tomography (PET) imaging using the tracer in the rat central nervous system are reported. The tracer structure, which contains a novel ß-fluoroethoxy phosphoester moiety, was designed as an insecticide-chemical nerve agent hybrid to optimize handling and the desired target reactivity. Radiosynthesis of the ß-fluoroethoxy tracer is described that utilizes a [(18)F]prosthetic group coupling approach. The imaging utility of the [(18)F]tracer is demonstrated in vivo within rats by the evaluation of its brain penetration and cerebral distribution qualities in the absence and presence of a challenge agent. The tracer effectively penetrates brain and localizes to cerebral regions known to correlate with the expression of the AChE target. Brain pharmacokinetic properties of the tracer are consistent with the formation of an OP-adducted acetylcholinesterase containing the fluoroethoxy tracer group. Based on the initial favorable in vivo qualities found in rat, additional [(18)F]tracer studies are ongoing to exploit the technology to dynamically probe organophosphate mechanisms of action in mammalian live tissues.

Delivery of macromolecules across oral mucosa from polymeric hydrogels is enhanced by electrophoresis (iontophoresis).

OBJECTIVE: To develop polymeric hydrogel delivery systems for iontophorseis transfer of large molecules across buccal (porcine) mucosa. METHODS: Three hydrogels (PVA, HPMC and PVA/HPMC) were prepared as stable gels (7 mm diameter/1.5 mm thick). Quantitative (8 and 36 h) assessment of porcine buccal mucosa and the three hydrogel delivery systems, using a diffusion cell in vitro model, was carried out by UV/vis spectroscopy with three model agents (3 and 10 kDa dextrans and 12 kDa parvalbumin). Passive and iontophoresis parameters were obtained. Experimental and theoretical data were compared. RESULTS: Iontophoresis (30 min, 1-8 h) significantly enhanced the delivery of all model agents across four single systems (hydrogels and buccal mucosa) and three sandwich systems (hydrogels on top of buccal mucosa), as confirmed by time lag factor/enhancement ratio (TLF/ER) data. The diffusion coefficients of model agents across buccal mucosa (×10(-13) m(2) s(-1)) were ~100 times lower than across single hydrogels (2.97-4.80×10(-11) m(2) s(-1)). Solubility values of all agents across hydrogels were similar, but lower across buccal mucosa. Permeability of parvalbumin was highest across PVA, and for both dextrans across PVA/HPMC. In sandwich systems TLFs were similar for all hydrogels, but significantly lower, and ERs significantly higher, than tissue alone. Experimental and theoretical TLF data were in reasonable agreement. SIGNIFICANCE: The in vitro data show that iontophoresis enhanced the delivery of large molecules across polymeric hydrogel systems and buccal mucosa. This creates the opportunity of new approaches to drug delivery and opens pathways to further research for delivering therapeutic agents topically and systemically.

Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model.

Microwave accelerated reaction system (MARS) technology provided a good method to obtain selective and open isoxazole ligands that bind to and inhibit the Sxc- antiporter. The MARS provided numerous advantages, including: shorter time, better yield and higher purity of the product. Of the newly synthesized series of isoxazoles the salicyl hydrazide 6 exhibited the highest level of inhibitory activity in the transport assay. A homology model has been developed to summarize the SAR results to date, and provide a working hypothesis for future studies.

Electrically induced transport of macromolecules through oral buccal mucosa.

OBJECTIVE: To investigate the feasibility of iontophoretic delivery of large molecules across buccal mucosa, and to establish its potential for enhanced drug delivery. METHODS: Qualitative (6h) and quantitative (8 and 36 h) assessment of porcine buccal mucosa, using a diffusion cell in vitro model, was carried out by fluorescent microscopy and UV/Vis spectroscopy respectively, with four fluorescently-labeled model species (3 and 10 kDa dextrans, 12 kDa parvalbumin and 66 kDa bovine serum albumin, BSA). Passive and iontophoresis parameters were obtained. The experimental iontophoresis data were compared with theoretical predictions. RESULTS: The two dextrans and parvalbumin showed enhanced permeation through buccal mucosa after anodal iontophoresis (1-6h). Passive diffusion and cathodal iontophoresis resulted in minimal permeation. BSA could not be measured by either mode. Iontophoretic delivery profiles compared to passive delivery, had reduced time lags (30-50 versus ~270 min) and increased flux (~37 times faster). Time lag factor/enhancement ratio (TLF/ER) data confirmed that iontophoresis significantly enhanced permeation. The diffusion coefficients (D, passive) for dextrans were significantly higher than for parvalbumin, with the converse obtained for solubility (C0); permeability coefficients (P) were similar for all three species. Potential differences (V) for the two higher kDa species were significantly higher than for the lowest kDa species. Experimental and theoretical data were in reasonable agreement. SIGNIFICANCE: The experimental and theoretical data, confirming enhanced delivery of the model species via iontophoresis, gave a suitable basis for its potential application in the mouth, in a clinical setting and opens pathways to further research for delivering precious drugs topically and systemically.

Some aspects of the formulation of alginate dental impression materials--setting characteristics and mechanical properties.

OBJECTIVE: To study the role of the various components of alginate dental impression materials. METHODS: Experimental materials were formulated and their physical properties characterized and compared to commercially available counterparts (Neocolloid, Palgat Plus and Blueprint Cremix). Properties examined were: dimensional stability and weight change in water and artificial saliva; setting behavior; Shore A hardness and tear energy. The role of magnesium oxide was also investigated. RESULTS: Weight changes in water and artificial saliva can be attributed to an initial thermodynamic potential owing to the ionic content of the alginate, causing water to diffuse into the material. Water is then driven back out following a reversal of this potential. Hardness results for experimental materials were within the range obtained from the commercial materials. The hardness value for an experimental formulation that did not contain magnesium oxide was lower than values from the other experimental materials that did. Tear energies for all three experimental materials were greater than those of the commercial products. There were statistically significant differences between the two experimental materials that contained magnesium oxide and one that did not. With regard to setting time, statistically significant differences were seen between commercial materials and two of the experimental materials. The experimental material that did not contain magnesium oxide had a considerably longer setting time than all of the other materials tested. SIGNIFICANCE: The key role of magnesium oxide in the setting reaction and the effect on hardness have been demonstrated and discussed.

The interaction of various liquids with long-term denture soft lining materials.

OBJECTIVES: To study the uptake of liquids, representative of those encountered orally, by long-term denture soft lining materials, and analyze the data in terms of appropriate theories. METHODS: Four proprietary and one experimental soft lining material were investigated, and the weight change presented as a function of time in both aqueous and organic fluids over the course of a year. A separate experiment determined the equilibrium swelling in ethanol of poly(ethyl methacrylate) and poly(methyl methacrylate). RESULTS: Uptake date for the five soft lining materials in various aqueous solution, coconut oil and HB307 are reported. The experimental value for the equilibrium swelling of poly(ethyl methacrylate) and poly(methyl methacrylate) in ethanol was reported to indicate the solubility parameter of the system. SIGNIFICANCE: The results have been analyzed by relevant theoretical models, which have been shown to explain the experimental data.

The effect of disinfecting solutions on the dimensional stability of dental alginate impression materials.

OBJECTIVES: Dimensional changes occur in set dental alginate impression materials when immersed in disinfecting solutions. In this contribution the dimensional changes of two alginates in two disinfecting solutions, and for two specimen thicknesses, have been studied. The results were analyzed theoretically. METHODS: The dimensional changes of two commercial alginates (Blueprint Cremix and Hydrogum), have been measured, in distilled water and two disinfecting solutions (Perform ID/sodium hypochlorite), using a traveling microscope, at 5 min intervals over a period of 1h. Samples of simple geometry have been studied, namely rectangular strips with thicknesses of 1.5 and 3mm, respectively. RESULTS: In all cases, both alginates continuously shrank with time, in the three immersion liquids, over the hour of measurement, indicating transfer of water from the alginate into the external water or disinfecting solution. The t(1/2) shrinkage plots were generally linear, but with an intercept on the t(1/2) axis, indicating the possibility of an initial expansion at very short times. In most cases, the ratios of slopes for both thicknesses were 1.33-1.54, in contrast to the theoretical value of 2. Perform ID however gave anomalous results for the 1.5mm thick samples. At 10 min their shrinkage was 1.34-1.72%, compared with -0.42% to 0.67% in the other two media. SIGNIFICANCE: The effects of thickness observed were not in accord with simple Fickian theory because of the various ions diffusing into and out of the alginate. Moreover, the water content of the alginate decreased consequent on the cross-linking process.

An experimental and theoretical study of the effect of sample thickness on the Shore hardness of elastomers.

OBJECTIVE: The Shore hardness test is a quick and convenient way to measure hardness of elastomers. The test specifies that the specimen should be at least 6mm thick; however, published work in the literature indicates that workers often use much thinner samples. The aim of this study was to investigate the effect of thickness on the measured hardness of a range of dental elastomers and develop a theoretical relationship to predict the effect. METHODS: 7 dental silicone elastomers were selected to give a range of hardness values. Shore A scale hardness measurements were made on standard thickness samples, and those of lower thicknesses. A theoretical analysis was derived, whereby the effect of thickness of the sample on its measured hardness can be predicted and was tested using the results obtained. RESULTS: The results show reasonable agreement between theoretical and experimental values. The measured Shore hardness increased inversely with thickness, the effect being most pronounced with thin samples. Results ranged from 66.3+/-1.6-80.9+/-0.4 for 1mm thick to 35.0+/-1.7-69.1+/-0.6 for the 6mm thickness. Ratio of the measured hardness of 1mm/6mm ranged from 1.97 for the softest material to 1.17 for the hardest. SIGNIFICANCE: Measurements obtained with a Shore A hardness tester on samples of less than the specified 6mm thickness will give erroneously high values, the error being greater as thickness decreases. The theoretical treatment proposed gives a basis on which data obtained from studies that used thinner specimens can be better analysed.

Inhibition of acetylcholinesterase by chromophore-linked fluorophosphonates.

Fluorophosphonate (FP) head groups were tethered to a variety of chromophores (C) via a triazole group and tested as FPC inhibitors of recombinant mouse (rMoAChE) and electric eel (EEAChE) acetylcholinesterase. The inhibitors showed bimolecular inhibition constants (k(i)) ranging from 0.3 x 10(5)M(-1)min(-1) to 10.4 x 10(5)M(-1)min(-1). When tested against rMoAChE, the dansyl FPC was 12.5-fold more potent than the corresponding inhibitor bearing a Texas Red as chromophore, whereas the Lissamine and dabsyl chromophores led to better anti-EEAChE inhibitors. Most inhibitors were equal or better inhibitors of rMoAChE than EEAChE. 3-Azidopropyl fluorophosphonate, which served as one of the FP head groups, showed excellent inhibitory potency against both AChE's ( congruent with 1 x 10(7)M(-1)min(-1)) indicating, in general, that addition of the chromophore reduced the overall anti-AChE activity. Covalent attachment of the dabsyl-FPC analog to rMoAChE was demonstrated using size exclusion chromatography and spectroscopic analysis, and visualized using molecular modeling.

The relationship between Shore hardness of elastomeric dental materials and Young's modulus.

OBJECTIVES: Hardness of elastomers can be directly related to Young's modulus, a relationship that was investigated in detail by Gent in a paper in 1958. The aim of this study was to test this relationship for 13 dental elastomers (12 silicone and 1 polyether) using the equation derived by Gent and one from BS 903 (1950) that accounts for departures at low values. METHODS: The dental elastomers were subjected to tensile testing and Shore A scale hardness measurements. Young's moduli were calculated from the hardness values using the Gent equation and the BS 903 equation. These calculated values were then compared with values derived experimentally from the tensile tests. RESULTS: Hardness values were in the range 30.2 (+/-0.5)-62.9 (+/-0.8) with the corresponding calculated modulus values in the range 1.1-4.1MPa and 0.9-4.3MPa for the Gent and modified equations, respectively. Young's modulus values derived from the tensile data were in the range 0.8 (+/-0.3)-4.1 (+/-0.3)MPa, showing good agreement with those calculated from the hardness values. Providing viscoelastic creep is minimal during the duration of the test, there is a reasonably well-defined relationship between Shore hardness and Young's modulus in the hardness range studied. SIGNIFICANCE: Simple, non-destructive hardness measurements can be used to determine Young's modulus values. Such values are needed in any calculations of stress distributions in soft lining materials, e.g. by FEA.

Assessment of the roles of serines 5.43(239) and 5.46(242) for binding and potency of agonist ligands at the human serotonin 5-HT2A receptor.

We assessed the relative importance of two serine residues located near the top of transmembrane helix 5 of the human 5-HT(2A) receptor, comparing the wild type with S5.43(239)A or S5.46(242)A mutations. Using the ergoline lysergic acid diethylamide (LSD), and a series of substituted tryptamine and phenethylamine 5-HT(2A) receptor agonists, we found that Ser5.43(239) is more critical for agonist binding and function than Ser5.46(242). Ser5.43(239) seems to engage oxygen substituents at either the 4- or 5-position of tryptamine ligands and the 5-position of phenylalkylamine ligands. Even when a direct binding interaction cannot occur, our data suggest that Ser5.43(239) is still important for receptor activation. Polar ring-substituted tryptamine ligands also seem to engage Ser5.46(242), but tryptamines lacking such a substituent may adopt an alternate binding orientation that does not engage this residue. Our results are consistent with the role of Ser5.43(239) as a hydrogen bond donor, whereas Ser5.46(242) seems to serve as a hydrogen bond acceptor. These results are consistent with the functional topography and utility of our in silico-activated homology model of the h5-HT(2A) receptor. In addition, being more distal from the absolutely conserved Pro5.50, a strong interaction with Ser5.43(239) may be more effective in straightening the kink in helix 5, a feature that is possibly common to all type A GPCRs that have polar residues at position 5.43.

1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists.

A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy-4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT(2A) receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream signaling pathways, and one exceptional compound was selected for testing in an in vivo drug discrimination model of hallucinogenesis. All compounds were examined in silico by virtual docking into a homology model of the 5-HT(2A) receptor. On the basis of these docking experiments, it was predicted that the R enantiomer of benzocyclobutene analogue 2 would be the most potent. Subsequent chemical resolution and X-ray crystallography confirmed this prediction, as (R)-2 proved to be equipotent to LSD in rats trained to discriminate LSD from saline. Thus, we propose that the conformation of 2 mimics the active binding conformation of the more flexible phenethylamine type hallucinogens. In addition, (R)-2 is one of the most potent and selective compounds yet discovered in the in vivo drug discrimination assay. Further, 2 was found to be a functionally selective agonist at the 5-HT(2A) receptor, having 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are correlated with arachidonic acid production, such functionally selective 5-HT(2A) receptor agonists may lack the intoxicating properties of hallucinogens such as LSD.

Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists.

Experiments were conducted to examine the molecular basis for the high affinity and potency of a new class of 5-HT(2A) receptor agonists, N-benzyl phenethylamines. Competition binding assays at several serotonin receptors confirmed that an N-arylmethyl substitution was necessary for affinity increases up to 300-fold over simple N-alkyl homologs, as well as enhanced selectivity for 5-HT(2A) versus 5-HT(2C) and 5-HT(1A) receptors. PI hydrolysis functional assays confirmed that these N-benzyl phenethylamines are potent and highly efficacious agonists at the rat 5-HT(2A) receptor. Virtual docking of these compounds into a human 5-HT(2A) receptor homology model indicated that the N-benzyl moiety might be interacting with Phe339((6.51)), whereas the phenethylamine portion was likely to be interacting with Phe340((6.52)). Experiments in h5-HT(2A) receptors with Phe339((6.51))L and Phe340((6.52))L mutations seem to support this hypothesis. Dramatic detrimental effects on affinity, potency, and intrinsic activity were observed with the Phe339((6.51))L mutation for all N-benzyl analogs, whereas most N-unsubstituted phenethylamines and traditional agonists were only weakly affected, if at all. Consistent with other published studies, the Phe340((6.52))L mutation detrimentally affected affinity, potency, and intrinsic activity of nearly all compounds tested, although a strong change in intrinsic activity was not seen with most N-aryl analogs. These data further validate the topology of our h5-HT(2A) receptor homology model. It is noteworthy that this study is the first to identify a hitherto unrecognized role for residue 6.51 in agonist activation of a serotonin G protein-coupled receptor (GPCR), whereas most previous reports have suggested a varied and sometimes contradictory role in homologous GPCRs.

C-(4,5,6-trimethoxyindan-1-yl)methanamine: a mescaline analogue designed using a homology model of the 5-HT2A receptor.

A conformationally restricted analogue of mescaline, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed using a 5-HT(2A) receptor homology model. The compound possessed 3-fold higher affinity and potency than and efficacy equal to that of mescaline at the 5-HT(2A) receptor. The new analogue substituted fully for LSD in drug discrimination studies and was 5-fold more potent than mescaline. Resolution of this analogue into its enantiomers corroborated the docking experiments, showing the R-(+) isomer to have higher affinity and potency and to have efficacy similar to that of mescaline at the 5-HT(2A) receptor.