Ali Tabatabaei

AC-260584, an orally bioavailable M1 muscarinic receptor allosteric agonist, improves cognitive performance in an animal model

The recent discovery of allosteric potentiators and agonists of the muscarinic M(1) receptor represents a significant advance in the muscarinic receptor pharmacology. In the current study we describe the receptor pharmacology and pro-cognitive action of the allosteric agonist AC-260584. Using in vitro cell-based assays with cell proliferation, phosphatidylinositol hydrolysis or calcium mobilization as endpoints, AC-260584 was found to be a potent (pEC(50) 7.6-7.7) and efficacious (90-98% of carbachol) muscarinic M(1) receptor agonist. Furthermore, as compared to orthosteric binding agonists, AC-260584 showed functional selectivity for the M(1) receptor over the M(2), M(3), M(4) and M(5) muscarinic receptor subtypes. Using GTPgammaS binding assays, its selectivity was found to be similar in native tissues expressing mAChRs to its profile in recombinant systems. In rodents, AC-260584 activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in the hippocampus, prefrontal cortex and perirhinal cortex. The ERK1/2 activation was dependent upon muscarinic M(1) receptor activation since it was not observed in M(1) knockout mice. AC-260584 also improved the cognitive performance of mice in the novel object recognition assay and its action is blocked by the muscarinic receptor antagonist pirenzepine. Taken together these results indicate for the first time that a M(1) receptor agonist selective over the other mAChR subtypes can have a symptomatically pro-cognitive action. In addition, AC-260584 was found to be orally bioavailable in rodents. Therefore, AC-260584 may serve as a lead compound in the development of M(1) selective drugs for the treatment of cognitive impairment associated with schizophrenia and Alzheimers disease.

Identification and Characterization of Novel Small-Molecule Protease-Activated Receptor 2 Agonists

We report the first small-molecule protease-activated receptor (PAR) 2 agonists, AC-55541 [N-[[1-(3-bromo-phenyl)-eth-(E)-ylidene-hydrazinocarbonyl]-(4-oxo-3,4-dihydro-phthalazin-1-yl)-methyl]-benzamide] and AC-264613 [2-oxo-4-phenylpyrrolidine-3-carboxylic acid [1-(3-bromo-phenyl)-(E/Z)-ethylidene]-hydrazide], each representing a distinct chemical series. AC-55541 and AC-264613 each activated PAR2 signaling in cellular proliferation assays, phosphatidylinositol hydrolysis assays, and Ca2+ mobilization assays, with potencies ranging from 200 to 1000 nM for AC-55541 and 30 to 100 nM for AC-264613. In comparison, the PAR2-activating peptide 2-furoyl-LIGRLO-NH2 had similar potency, whereas SLIGRL-NH2 was 30 to 300 times less potent. Neither AC-55541 nor AC-264613 had activity at any of the other PAR receptor subtypes, nor did they have any significant affinity for over 30 other molecular targets involved in nociception. Visualization of EYFP-tagged PAR2 receptors showed that each compound stimulated internalization of PAR2 receptors. AC-55541 and AC-264613 were well absorbed when administered intraperitoneally to rats, each reaching micromolar peak plasma concentrations. AC-55541 and AC-264613 were each stable to metabolism by liver microsomes and maintained sustained exposure in rats, with elimination half-lives of 6.1 and 2.5 h, respectively. Intrapaw administration of AC-55541 or AC-264613 elicited robust and persistent thermal hyperalgesia and edema. Coadministration of either a tachykinin 1 (neurokinin 1) receptor antagonist or a transient receptor potential vanilloid (TRPV) 1 antagonist completely blocked these effects. Systemic administration of either AC-55541 or AC-264613 produced a similar degree of hyperalgesia as was observed when the compounds were administered locally. These compounds represent novel small-molecule PAR2 agonists that will be useful in probing the physiological functions of PAR2 receptors.

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

We discovered structurally novel human calcium-sensing receptor (CaSR) allosteric agonists and compared their pharmacology to phenylalkylamine calcimimetics. 1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol (AC-265347) activated CaSR signaling in cellular proliferation and phosphatidylinositol (PI) hydrolysis assays with potencies of 30 and 10 nM, respectively. (S)-1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(S)-AC-265347], the S-enantiomer of AC-265347, was approximately 10- to 20-fold more potent than (R)-1-benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(R)-AC-265347]. The phenylalkylamines cinacalcet and calindol had activity similar to that of AC-265347 in cellular proliferation assays but less activity in PI assays. All compounds had reduced activity when extracellular Ca2+ was removed, indicating that they cooperate with Ca2+ to activate CaSRs, and all activated CaSR isoforms with the N-terminal extracellular domain deleted, indicating that they interact with the transmembrane domains. In both cases, AC-265347 and therefore (S)-AC-265347 were significantly more efficacious than the phenylalkylamines. Mutations E837A7.39 and I841A7.43 strongly reduced phenylalkylamine-induced signaling, but not AC-265347- or (S)-AC-265347-induced signaling, suggesting different modes of binding. AC-265347 and (S)-AC-265347 stimulated significantly greater responses than cinacalcet or calindol at each of four loss-of-function human polymorphic CaSR variants. AC-265347 did not inhibit the CYP2D6 cytochrome P450 isozyme, unlike cinacalcet, which is a potent CYP2D6 inhibitor. In rats, AC-265347, (S)-AC-265347, and (R)-AC-265347 each reduced serum parathyroid hormone (PTH) with a rank order potency correlated with their in vitro potencies. AC-265347 and (S)-AC-265347 also reduced plasma ionizable calcium ([Ca2+]o). AC-265347 was orally active, and its plasma concentrations correlated well with its effects on serum PTH. Thus, these highly efficacious CaSR allosteric agonists represent leads for developing therapeutic agents with potential advantages over existing therapies.

Synthesis and Evaluation of Dibenzothiazepines: A Novel Class of Selective Cannabinoid-1 Receptor Inverse Agonists

A novel class of CB1 inverse agonists was discovered. To efficiently establish structure-activity relationships (SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were evaluated in a mammalian cell-based functional assay and in radioligand binding assays expressing recombinant human cannabinoid receptors (CB1 and CB2). In general, all of the compounds exhibited high binding selectivity at CB1 vs CB2 and the general SAR revealed a lead compound 11-(4-chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12e) which showed excellent in vivo activity in pharmacodynamic models related to CB1 receptor activity. The low solubility that hampered the development of 12e was solved leading to a potential preclinical candidate 11-(3-chloro-4-fluorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12h).

Synthesis, Structure−Activity Relationships, and Characterization of Novel Nonsteroidal and Selective Androgen Receptor Modulators

Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats. In addition to compound 1, a number of potent antiandrogens were discovered from the same series of compounds whereof one compound, 13, had antagonist activity at the AR T877A mutant involved in prostate cancer.

Evaluation of Posterior Lens Capsule by 20-MHz Ultrasound Probe in Traumatic Cataract

PURPOSE To investigate the accuracy of echography with a 20-MHz probe for evaluation of posterior lens capsule in traumatic cataract before surgery. DESIGN Prospective interventional case series. METHODS This study consisted of 43 eyes with traumatic cataract that were scheduled to undergo surgery. In all cases, cataract was dense enough to prevent visualization of the posterior lens capsule. Echography was performed using a 20-MHz probe to detect rupture of the posterior lens capsule. All patients subsequently underwent cataract extraction and intraoperative findings of the posterior lens capsule were compared with the preoperative echographic findings. RESULTS This study included 43 eyes of 43 patients (38 men and 5 women) with a mean age of 35.6 ± 15.3 years (range, 4-68 years). The trauma was either blunt (4 eyes) or sharp (39 eyes); there was closed globe injury in 2 eyes and open globe injury in 41 eyes. By 20-MHz echography, posterior border of the crsytalline lens was clearly visualized in all 43 eyes. By 20-MHz echographic imaging, rupture of the posterior lens capsule was identified in 17 eyes (39.5%). During cataract surgery, it was noted that 14 eyes (32.6%) had rupture of the posterior lens capsule. Sensitivity, specificity, positive predictive value, and negative predictive value were 93%, 86%, 76%, and 96%, respectively, for 20-MHz echography to detect rupture of the posterior lens capsule. Also, the positive likelihood ratio, negative likelihood ratio, and odds ratio were 6.7, 0.08, and 81, respectively. CONCLUSION Echography with 20-MHz probe is an accurate imaging modality for detection of posterior lens capsule rupture in traumatic cataract preoperatively. This technique helps ophthalmologists have an appropriate surgical plan before operating.

Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders

A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.

A controlled study of amniotic membrane transplantation for acute Pseudomonas keratitis.

OBJECTIVE To evaluate the efficacy of amniotic membrane transplantation (AMT) to improve the outcomes of acute Pseudomonas keratitis as compared with a control group. DESIGN Prospective interventional case series with retrospective controls. PARTICIPANTS We studied 14 eyes with Pseudomonas keratitis as the AMT group and 11 eyes with Pseudomonas keratitis as the control group. METHODS Eyes in the AMT group were treated with antibiotic therapy followed by single-layer AMT at 2 to 3 days. Eyes in the control group received only antibiotic therapy. Patients were followed for 11.1 ± 2.4 months. RESULTS In the AMT group, pain significantly decreased from a mean score of 2.4 ± 0.5 preoperatively to 1.1 ± 0.9 at day 2 postoperatively (p < 0.001). Corneal epithelial defects healed completely within 13.2 ± 2.6 days in the AMT group compared with 15.5 ± 3.4 days in the control group (p = 0.07). At final follow-up visits, the sizes of corneal opacity and deep neovascularization were not different between the 2 groups. However, the mean score for density of the corneal opacity was significantly less in the AMT group compared with the control group (2.1 ± 0.4 vs 2.5 ± 0.7, respectively, p = 0.04). Although the best corrected visual acuity using hard contact lenses was not different between the 2 groups, uncorrected visual acuity was better in the AMT group (0.45 ± 0.22 logMAR) than in the control group (0.71 ± 0.32 logMAR, p = 0.03). No patient in either group developed significant corneal thinning or perforation. CONCLUSIONS AMT in acute Pseudomonas keratitis was associated with immediate pain relief, less density of the final corneal opacity, and better uncorrected visual acuity at the final follow-up visit.

Discovery of potential antipsychotic agents possessing pro-cognitive properties

Current antipsychotic drug therapies for schizophrenia have limited efficacy and are notably ineffective at addressing the cognitive deficits associated with this disorder. The present study was designed to develop effective antipsychotic agents that would also ameliorate the cognitive deficits associated with this disease. In vitro studies comprised of binding and functional assays were utilized to identify compounds with the receptor profile that could provide both antipsychotic and pro-cognitive features. Antipsychotic and cognitive models assessing in vivo activity of these compounds included locomotor activity assays and novel object recognition assays. We developed a series of potential antipsychotic agents with a novel receptor activity profile comprised of muscarinic M1 receptor agonism in addition to dopamine D2 antagonism and serotonin 5-HT2A inverse agonism. Like other antipsychotic agents, these compounds reverse both amphetamine and dizocilpine-induced hyperactivity in animals. In addition, unlike other antipsychotic drugs, these compounds demonstrate pro-cognitive actions in the novel object recognition assay. The dual attributes of antipsychotic and pro-cognitive actions distinguish these compounds from other antipsychotic drugs and suggest that these compounds are prototype molecules in the development of novel pro-cognitive antipsychotic agents.

Accuracy of 3 imaging modalities for evaluation of the posterior lens capsule in traumatic cataract

Purpose To compare the accuracy of 3 imaging modalities for preoperative evaluation of the posterior lens capsule in traumatic cataract. Setting Farabi Eye Hospital, Tehran, Iran. Design Case series. Methods The study comprised eyes with traumatic cataract opaque enough to prevent visualization of the posterior lens capsule on slitlamp examination. To detect posterior lens capsule rupture before surgery, imaging was performed with 20 MHz echography (Eye Cubed), anterior segment optical coherence tomography (AS‐OCT) (Visante model 1000), and Scheimpflug imaging (Pentacam). All patients subsequently had cataract extraction, and the intraoperative findings of the posterior lens capsule were compared with the preoperative findings of the imaging modalities. Results The study enrolled 21 eyes of 21 patients (20 men, 1 woman) with a mean age of 31.5 years ± 1.45 (SD). The nature of trauma was blunt (5 eyes) or sharp (16 eyes). To detect posterior lens capsule rupture, the sensitivity and specificity were, respectively, 80% and 86% for 20 MHz echography, 71% and 77% for AS‐OCT, and 62% and 57% for Scheimpflug imaging (95% confidence intervals: sensitivity, 30.00‐90.32; specificity, 54.81‐92.95). Insufficient resolution for posterior lens capsule evaluation occurred in 33.3% cases for AS‐OCT and 57.1% cases for Scheimpflug imaging. The accuracy of 20 MHz echography, AS‐OCT, and Scheimpflug imaging was 76.1%, 61.9%, and 42.9%, respectively. Conclusion In the evaluation of the posterior lens capsule in eyes with traumatic cataract, 20 MHz echography had higher accuracy than AS‐OCT and Scheimpflug imaging. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.