Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

/pdf/crystal-structure-of-the-u-opioid-receptor-bound-to-a-3114f9v1hs.pdf

Crystal structure of the µ-opioid receptor bound to a morphinan antagonist

The formation and duration of binary receptor−ligand complexes are fundamental to many physiologic processes. Most often, the effectiveness of interaction between a receptor and its ligand is quantified in terms of closed system, equilibrium affinity measurements, such as IC50 and Kd. In the context of in vivo biology, however, the extent and duration of responses to receptor−ligand interactions depend greatly on the time period over which the ligand is in residence on its receptor. Here we define receptor−ligand complex residence time in quantitative terms and describe its significance to biological function. Examples of the importance of residence time are presented for natural ligands of different receptor types. The impact of residence time on the optimization of potential ligands as drugs for human medicine is also described.

Residence time of receptor-ligand complexes and its effect on biological function.

The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRABACh (GPCR-activation-based ACh) sensor to achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor. Using this sensor, we revealed compartmental ACh signals in the olfactory center of transgenic flies in response to external stimuli including odor and body shock. Using fiber photometry recording and two-photon imaging, our ACh sensor also enabled sensitive detection of single-trial ACh dynamics in multiple brain regions in mice performing a variety of behaviors.

An optimized acetylcholine sensor for monitoring in vivo cholinergic activity.

BACKGROUND A study was undertaken to evaluate and compare the efficacy and safety of tiotropium and ipratropium during long term treatment in patients with stable chronic obstructive pulmonary disease (COPD).

METHODS 288 patients of mean (SD) age 65 (8) years and forced expiratory volume in one second (FEV1) 41 (12)% predicted participated in a 14 centre, double blind, double dummy, parallel group study and were randomised after a run in period of two weeks to receive either tiotropium 18 μg once daily from a dry powder inhaler (HandiHaler; two thirds of patients) or ipratropium 40 μg four times daily from a metered dose inhaler (one third of patients) for a period of 13 weeks. Outcome measures were lung function, daily records of peak expiratory flow (PEF), and the use of concomitant salbutamol. FEV1and forced vital capacity (FVC) were measured one hour before and immediately before inhalation (mean value of the two measurements on test day 1 was the baseline value while on all other test days it was known as the trough FEV1 and FVC), and 0.5, 1, 2, 3, 4, 5, and 6 hours after inhalation of the study drug on days 1, 8, 50, and 92.

RESULTS During treatment tiotropium achieved a significantly greater improvement than ipratropium (p<0.05) in trough, average, and peak FEV1levels and in trough and average FVC levels. The trough FEV1 response on days 8, 50, and 92 ranged between 0.15 l (95% CI 0.11 to 0.19) and 0.16 l (95% CI 0.12 to 0.20) for tiotropium and between 0.01 l (95% CI –0.03 to 0.05) and 0.03 l (95% CI 0.01 to 0.07) for ipratropium. The trough FVC response on days 8, 50, and 92 ranged between 0.34 l (95% CI 0.28 to 0.40) and 0.39 l (95% CI 0.31 to 0.47) for tiotropium and between 0.08 l (95% CI 0.00 to 0.16) and 0.18 l (95% CI 0.08 to 0.28) for ipratropium. On all test days tiotropium produced a greater improvement in FEV1than ipratropium starting three hours after inhalation (p<0.05). During treatment weekly mean morning and evening peak expiratory flow (PEF) was consistently better in the tiotropium group than in the ipratropium group, the difference in morning PEF being significant up through week 10 and in evening PEF up through week 7 of treatment (p<0.05). The use of concomitant salbutamol was also lower in the tiotropium group (p<0.05). The only drug related adverse event was dry mouth (tiotropium 14.7%, ipratropium 10.3% of patients).

CONCLUSIONS Tiotropium in a dose of 18 μg inhaled once daily using the HandiHaler was significantly more effective than 40 μg ipratropium four times daily in improving trough, average, and peak lung function over the 13 week period. The safety profile of tiotropium was similar to ipratropium. These data support the use of tiotropium as first line treatment for the long term maintenance treatment of patients with airflow obstruction due to COPD.

https://thorax.bmj.com/content/thoraxjnl/55/4/289.full.pdf

A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease

Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic bronchodilator that has muscarinic M(1) and M(3) receptor subtype selectivity. A multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the dose-response characteristics of tiotropium inhalation powder given once daily to stable patients with chronic obstructive pulmonary disease (COPD). Patients (mean FEV(1) = 1.08 L [42% predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 microg tiotropium once daily at noon for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients measured and recorded their peak expiratory flow rates (PEFRs) three times each day. Significant dose-related improvement in FEV(1) and significant improvement in FVC occurred within 1 h after the first dose of tiotropium as compared with placebo. Over the 29 d of the study, all doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h after the previous dose and just before the next dose of tiotropium), peak, and 6-h postdose average FEV(1) and FVC, and in PEFR, without a significant difference among the different doses investigated. PEFR gradually returned to pretreatment baseline levels over a 3-wk evaluation period following the discontinuation of tiotropium. The overall safety profile for the tiotropium doses was similar to that for placebo. In summary, tiotropium was shown to be safe and effective in doses ranging from 4.5 to 36 microg delivered once daily. The improvements in spirometry with once-daily dosing confirm the long duration of action of tiotropium reported in single-dose studies, and its sustained improvement of spirometric measures over the 1 mo of testing in the study points to utility of tiotropium as a maintenance bronchodilator for patients with COPD. On the basis of the comparable bronchodilator response at doses from 9 to 36 microg, and advantages suggested by the safety profile at doses below 36 microg in this study, a dose of 18 microg once daily was selected for use in long-term studies of the safety and efficacy of tiotropium.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.161.4.9903044

Long-Acting Bronchodilation with Once-Daily Dosing of Tiotropium (Spiriva) in Stable Chronic Obstructive Pulmonary Disease

Ba 679 BR, a novel long-acting anticholinergic bronchodilator

Compounds of formula ##STR1## wherein the substituents are defined hereinbelow, useful in the treatment of bronchospasm are described.

New quaternary ammonium compounds, their preparation and use

Compounds of the formula ##EQU1## wherein R1 is allyl, allyloxy or chlorine, R2 is hydrogen or methyl, R3 is hydrogen, alkyl of 1 to 5 carbon atoms or benzyl, and n is an integer from 2 to 6, inclusive, Provided, however, that when R1 is allyl or allyloxy, R2 is hydrogen; and their non-toxic, pharmacologically acceptable acid addition salts; the compounds as well as their salts are useful as β-adrenergic blocking agents and hypotensives.

N,N'bis-(3-phenoxy-2-hydroxy-propyl)-alkylenediamines and salts thereof

Compounds of the formula ##STR1## WHEREIN R 1 is hydrogen or methyl, m is 0 or an integer from 1 to 8, inclusive, and Ar is ##STR2## WHERE R is hydrogen or acyl, and R 2 is hydrogen or --OR, as defined above, ##STR3## WHERE R has the meanings defined above, and R 3 is hydroxy-lower alkyl, --NH--CO--R 4 , --NH--SO 2 --R 5 , --CH 2 --NH--CO--R 4 , --CH 2 --NH--SO 2 --R 5 or --CH 2 --NH--CO--NH--R 4 , where R 4 is hydrogen or lower alkyl, and R 5 is lower alkyl or di-lower alkyl-amino, ##STR4## WHERE R 6 is hydrogen, amino or hydroxyl, X is chlorine or bromine, and Y is hydrogen, chlorine or bromine or ##STR5## WHERE R has the meanings defined above, and A is a saturated or unsaturated 5- to 6-membered ring, And their non-toxic, pharmacologically acceptable acid addition salts; the compounds as well as their salts are useful as bronchospasmolytics, uterine spasmolytics, antipruritics and antiallergics

N,N'-bis-[(β-hydroxy-β-phenyl)-ethyl]-polymethylenediamines and salts thereof

Racemic or optically active compounds of the formula ##EQU1## wherein R 1 is hydrogen, halogen, alkyl or 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and R 2 is straight or branched hydroxyalkyl of 3 to 6 carbon atoms, And non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as the salts are useful β-adrenergic receptor blocking agents and hypotensives.

1-(Cyano-phenoxy)-2-hydroxy-3-hydroxyalkylamino-propanes and salts thereof

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