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Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients with OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage. The development of OIH and tolerance tend to occur simultaneously and, thus, present a challenge when studying the molecular mechanisms driving each phenomenon. We tested the hypothesis that a G protein-biased µ -opioid peptide receptor (MOPR) agonist would not induce symptoms of OIH, such as mechanical allodynia, following chronic administration. We observed that the development of opioid-induced mechanical allodynia (OIMA), a model of OIH, was absent in β -arrestin1 -/- and β -arrestin2 -/- mice in response to chronic administration of conventional opioids such as morphine, oxycodone and fentanyl, whereas tolerance developed independent of OIMA. In agreement with the β -arrestin knockout mouse studies, chronic administration of TRV0109101, a G protein-biased MOPR ligand and structural analog of oliceridine, did not promote the development of OIMA but did result in drug tolerance. Interestingly, following induction of OIMA by morphine or fentanyl, TRV0109101 was able to rapidly reverse allodynia. These observations establish a role for β -arrestins in the development of OIH, independent of tolerance, and suggest that the use of G protein-biased MOPR ligands, such as oliceridine and TRV0109101, may be an effective therapeutic avenue for managing chronic pain with reduced propensity for opioid-induced hyperalgesia., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Drug discovery targeting G protein-coupled receptors (GPCRs) is no longer limited to seeking agonists or antagonists to stimulate or block cellular responses associated with a particular receptor. GPCRs are now known to support a diversity of pharmacological profiles, a concept broadly referred to as functional selectivity. In particular, the concept of ligand bias, whereby a ligand stabilizes subsets of receptor conformations to engender novel pharmacological profiles, has recently gained increasing prominence. This review discusses how biased ligands may deliver safer, better tolerated, and more efficacious drugs, and highlights several biased ligands that are in clinical development. Biased ligands targeting the angiotensin II type 1 receptor and the μ opioid receptor illustrate the translation of the biased ligand concept from basic biology to clinical drug development., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The concept of "ligand bias" at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical μ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in β-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased μ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased μ opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain.

A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves a benzannulation based on the reaction of cyclobutenones with ynamides. This cascade process proceeds via a sequence of four pericyclic reactions and furnishes a multiply substituted aniline derivative which can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in a concise formal total synthesis of the anticancer agents (+)-FR900482 and (+)-FR66979 is described.

A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V(1a)- and good V(2)-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program's mixed V(1a)/V(2)-receptor antagonist standard., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A series of tricyclic anilinopyrimidines were synthesized and evaluated as IKKbeta inhibitors. Several analogues, including tricyclic phenyl (10, 18a, 18c, 18d, and 18j) and thienyl (26 and 28) derivatives were shown to have good in vitro enzyme potency and excellent cellular activity. Pharmaceutical profiling of a select group of tricyclic compounds compared to the non-tricyclic analogues suggested that in some cases, the improved cellular activity may be due to increased clog P and permeability., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A "ring expansion-annulation strategy" for the synthesis of substituted azulenes is described based on the reaction of beta'-bromo-alpha-diazo ketones with rhodium carboxylates. The key transformation involves an intramolecular Buchner reaction followed by beta-elimination of bromide, tautomerization, and in situ trapping of the resulting 1-hydroxyazulene as a carboxylate or triflate ester. Further synthetic elaboration of the azulenyl halide and sulfonate annulation products can be achieved by employing Heck, Negishi, Stille, and Suzuki coupling reactions. Reaction of the azulenyl triflate 84 with pinacolborane provides access to the azulenylboronate 91, which participates in Suzuki coupling reactions with alkenyl and aryl iodides. The application of these coupling reactions to the synthesis of biazulenes, terazulene 101, and related oligoazulenes is described, as well as the preparation of the azulenyl amino acid derivative 110.

[structure: see text]. A new strategy for the synthesis of substituted azulenes is reported, based on the reaction of beta'-bromo-alpha-diazo ketones with rhodium carboxylates. The key transformation involves intramolecular addition of a rhodium carbenoid to an arene pi-bond, electrocyclic ring opening, beta-elimination, tautomerization, and trapping to produce 1-hydroxyazulene derivatives. The synthetic utility of the method is enhanced by the ability of the triflate derivatives to participate in Suzuki coupling reactions, as illustrated in a synthesis of the antiulcer drug egualen sodium (KT1-32).

Background: The natural history of thyroid associated ophthalmopathy is poorly documented, although it is widely thought that many cases improve spontaneously with time. This has important implications in the management of patients and is also a critical factor when assessing the effects of different treatments., Objective: To document the natural history of thyroid associated ophthalmopathy, 59 patients were studied longitudinally and the severity of eye disease documented at regular intervals., Methods: Fifty-nine patients with thyroid associated ophthalmopathy who had not received immunosuppressive or surgical treatment for their eye disease, were recruited from a combined thyroid-eye clinic. They were assessed at presentation and at 3-6-monthly intervals for a median of 12 months. The eyes were assessed by separate and objective measurements relating to the status of the eyelids, cornea, extraocular muscles, proptosis and optic nerve function. In addition, a scoring system based on the above measurements was used to grade the overall severity of eye disease., Results: Thirteen patients (22%) improved substantially, 25 patients (42.4%) showed minor improvement, 13 patients (22%) did not change, and 8 patients (13.5%) deteriorated progressively, to the extent that immunosuppressive treatment was considered to be necessary., Conclusions: A significant proportion of patients with thyroid associated ophthalmopathy (64.4% in the present series) improve spontaneously so serial assessment plays an important part in deciding which patients require immunosuppressive treatment. These findings also support the view that clinical trials designed to test the efficacy of new treatments in thyroid associated ophthalmopathy should be scrupulously controlled to allow for the natural tendency towards remission.

Background: The pathogenesis of thyroid-associated ophthalmopathy is thought to be autoimmune, although environmental and genetic factors are also considered to be important. As the morbidity of thyroid-associated ophthalmopathy is considerable and treatment often unsatisfactory, there a need to identify possible predisposing factors., Objective: The study was undertaken in order to ascertain the relationship between age, gender and severity of thyroid-associated ophthalmopathy., Patients: One hundred and one consecutive patients with thyroid-associated ophthalmopathy who presented over a period of 5 years to a combined thyroid-eye clinic., Methods: Patients were assessed by grading their inflammatory signs and degree of diplopia, and by measurement of exophthalmos, palpebral aperture, differential intraocular pressure, and visual acuity. On the basis of the above an ophthalmopathy index was devised to grade the overall severity of eye disease., Results: The mean age was 49.2 years (SD 13.4), the female-to-male ratio was 4.05, and mean ophthalmopathy index 6.49 (SD 3.3). Optic nerve compression was present in 9.9% of patients. There was a positive relationship between age and ophthalmopathy index (P < 0.001); after correcting for age, males had an average ophthalmopathy index 41% greater than that of females., Conclusion: There is an association between severity of thyroid-associated ophthalmopathy and (i) advancing age and (ii) female-to-male ratio, which has not been previously described. Patients over the age of 60 (particularly males) with Graves' disease appear to be at risk of developing severe eye disease.

Azathioprine is used in the treatment of thyroid-associated ophthalmopathy, but its effectiveness has not been evaluated. In the present study 20 patients with moderately severe ophthalmopathy were recruited; 10 patients received azathioprine and the other 10 matched patients served as controls. During the treatment period (lasting 1 year) and 1 year later, no changes were detected in exophthalmometer readings, visual acuity or measurement of palpebral aperture. Differential intraocular pressure fell with time in both groups. Azathioprine treatment did not significantly influence these parameters, although it did induce significant decrease in thyroid microsomal antibodies and in thyroid-stimulating hormone binding inhibiting immunoglobulin index. The study demonstrates that thyroid-associated ophthalmopathy of moderate severity, often improves with time without treatment. Azathioprine is not an effective treatment for patients with moderately severe thyroid-associated ophthalmopathy. The study emphasises the necessity for an adequately matched control population in the evaluation of therapy.

Twenty patients with moderately severe ophthalmopathy due to Graves' disease or ophthalmic Graves' disease were treated by supervoltage orbital radiotherapy generated by a linear accelerator. Seven patients (35%) showed some response within 3 weeks of the treatment, four patients (20%) improved minimally while nine patients (45%) were unchanged. Improvement was noted mainly in soft tissue changes while proptosis decreased in only four patients. With one exception, ophthalmoplegia did not improve after the radiotherapy. The benefit obtained with the treatment was not impressive.

Patients with hyperprolactinemia may be managed by pituitary surgery or irradiation, bromocriptine treatment, or a combination of these methods, and some patients remain untreated. Little is known of the long-term consequences of some of these therapeutic regimens. Forty-six hyperprolactinemic patients (40 female and six male) managed solely with bromocriptine or no treatment over a period of 12 months to six years were therefore evaluated in this study. Nine patients with radiologically normal pituitary fossae were untreated and 10 received bromocriptine, 7.5 to 10 mg daily, while 20 patients with radiologic evidence of a pituitary tumor were treated with bromocriptine, generally 10 to 20 mg daily. Patients were assessed clinically, biochemically, and radiologically before treatment and at least six weeks after discontinuation of therapy. A further seven patients were similarly assessed before and after eight bromocriptine-induced pregnancies. Symptoms persisted in the untreated group of nine patients, although menstruation returned in four of the females with previous amenorrhea; serum prolactin levels remained elevated, other pituitary function did not change, and pituitary fossae remained normal radiologically. In all patients treated with bromocriptine, symptoms improved irrespective of radiologic findings on the pituitary, and were abolished in 67 percent during treatment associated with a decrease in serum prolactin levels in all, and a return of levels to within normal limits in 80 percent of patients. Persistent side effects were usually dose-related, but remained troublesome in 13 percent. Bromocriptine-induced tumor regression was evident radiologically in all patients with suprasellar tumor tissue and in some with purely intrasellar adenomas. This effect occurred rapidly and persisted or increased throughout follow-up. On discontinuation of treatment, prolactin levels remained significantly lower than before therapy (mean 2,934 versus 5,052 mU/liter, p less than 0.05) but were within the normal range in only two patients. Other pituitary function was unaltered, or improved in some patients with definite tumors. Bromocriptine-induced pregnancy produced no permanent change in clinical, biochemical, or radiologic status. Long-term bromocriptine treatment for hyperprolactinemia is thus highly effective in alleviating symptoms and suppressing prolactin secretion, and induces persistent tumor regression on treatment without deterioration of other pituitary function in patients with macroadenomas. On discontinuation of therapy, however, hyperprolactinemia usually recurs, and treatment may therefore need to be continued for years.

Eleven euthyroid patients with severe Graves' eye disease were treated with intravenous methylprednisolone and followed up for six months or more by ophthalmological assessment, orbital computed tomography (CT), photographs, and antibody measurements. Papilloedema resolved in the single patient in whom it was present; visual acuity was abnormal in seven eyes initially and in only one eye after treatment; the intraocular pressure differential, which reflects muscle dysfunction, was initially abnormal in 18 eyes but showed a progressive and distinct improvement; nine patients showed substantial improvement in inflammatory signs. Exophthalmos improved early after treatment, but this improvement was not maintained. Orbital CT showed a pronounced reduction in the bulk of eye muscles after treatment in eight of nine patients. Autoantibodies to the thyroid stimulating hormone receptor declined. Adverse effects were trivial. Thus eight patients showed a clear response to intravenous methylprednisolone as judged by ophthalmic assessment and CT scan. The two patients who showed little response and one who had none all had a long history (more than a year) of ophthalmopathy. Results were better than those with oral steroids and adverse effects less. Treatment of Graves' eye disease is more likely to be effective if given early; patients should be referred promptly to specialist centres, where treatment with intravenous methylprednisolone should be considered.

The long-term sequelae of external pituitary irradiation alone or in combination with surgery and/or bromocriptine therapy have been studied in 14 patients with large prolactinomas over an observation period of 6-22 years (mean 13 years). Galactorrhoea was abolished in four of the five females with this symptom, but menstrual disturbance persisted in five of six patients. Sexual function was normal without sex hormone replacement in only one of the eight males after treatment. Neurological deficits were abolished or improved by treatment in all 9 patients with this presentation. Serum prolactin levels declined after treatment (P less than 0.001) and fell to within the normal range off bromocriptine therapy in six of the 14 patients at a mean of 9 years (range 5-17 years) after radiotherapy. All patients had anterior pituitary deficiency of some degree at reassessment, and 13 required replacement treatment. Serial skull radiographs revealed remineralization of the fossa floor in five patients and a decrease in fossa size in three. All five patients who did not also have surgery had evidence of tumour shrinkage without bromocriptine treatment (on CT scan or metrizamide cisternography). Fourth generation CT scans on completion of the study revealed a decrease in tumour mass in all patients, with varying degrees of empty sella in 13 and a cystic intrasellar tumour in the remaining one. Residual tumour was demonstrated in 10 patients, three of whom had normal serum prolactin levels, while one patient without visible tumour had persistent hyperprolactinaemia. Radiotherapy, alone or in combination with surgery and bromocriptine, effectively decreases prolactin secretion and tumour size in patients with large prolactinomas at the expense of other anterior pituitary function. Circulating prolactin levels are a poor marker of residual tumour volume.

A family in the north-east of England with Anderson--Fabry's disease is presented. Alpha-galactosidase activity in plasma and white cells was significantly reduced in three adult male members of the family. One of them had an abnormal chromosome karyotype pattern with an extra Y chromosome (47,XYY) and he was clinically less severely affected than his brothers. Coincidentally five other members of the family suffered from a form of familial spastic paraplegia.

Assessment was made of 5% local guanethidine in treating eye manifestations in euthyroid patients with either treated thyrotoxicosis or ophthalmic Graves's disease. In a double-blind crossover study guanethidine caused greater improvement in lid retraction than a control solution. A long-term study showed that this improvement was maintained. A much lower incidence of side-effects was noted with 5% guanethidine than with 10% solution.

The value of electronystagmography (ENG) and of tonography in monitoring the beneficial effect of edrophonium chloride (Tensilon) on the extraocular muscles in myasthenia gravis has been assessed. Studies were performed on 17 patients with myasthenia gravis and on 18 control subjects, of whom nine had extraocular muscle weakness due to myopathic or neurogenic lesions.Electronystagmography recorded the repetitive following movements of the eyes elicited during optokinetic nystagmus. Neuromuscular fatigue with the subsequent beneficial response to Tensilon was clearly seen in 50% of patients with myasthenia. False positive responses were not seen in control subjects but in many of these, as in the remaining myasthenic patients, the amplitude and rate of nystagmus seen in the ENG was very variable. These difficulties suggest that the ENG is of limited value as a diagnostic test in myasthenia gravis.Tonography, recording the intraocular pressure of the eye continuously over four minutes, was found to be of considerable value. We found that the intraocular pressure fell on average by 1·6 to 1·8 mm Hg over a one minute period in the control recordings but increased by a mean of 1·6 mm Hg in patients with myasthenia, with a peak effect 35 seconds after Tensilon. In only one patient was there a complete failure of response. This patient, and also another woman who showed a less striking response, had severe myasthenia with a fixed ocular weakness. It is suggested that an absence of any increase in tension with Tensilon may be seen in patients with permanent neostigmine-resistant myopathic change. A small false positive response was seen on one occasion only in a patient with a sympathetic nerve lesion.Tensilon tonography, as a simple painless procedure, would appear to be of considerable value in the diagnosis of ocular myasthenia and also as a diagnostic test in the exclusion of myasthenia as a cause of isolated extraocular neuromuscular weakness.

The eyes of 39 patients who had received allogenic renal transplants were examined for signs of disease. Nine (23%) had early posterior subcapsular cataracts, two (5%) developed acute cytomegalovirus retinitis, and one developed steroid-induced glaucoma. The lesions which were found were all attributable to the immunosuppressive drug therapy. Thirty-five (87%) had detectable complement-fixing antibodies to cytomegalovirus.