Key aspects of modern GPCR drug discovery.

G-protein-coupled receptors (GPCRs) are the largest and most versatile cell surface receptor family with a broad repertoire of ligands and functions. We've learned an enormous amount about discovering drugs of this receptor class since the first GPCR was cloned and expressed in 1986, such that it's now well-recognized that GPCRs are the most successful target class for approved drugs. Here we take the reader through a GPCR drug discovery journey from target to the clinic, highlighting the key learnings, best practices, challenges, trends and insights on discovering drugs that ultimately modulate GPCR function therapeutically in patients. The future of GPCR drug discovery is inspiring, with more desirable drug mechanisms and new technologies enabling the delivery of better and more successful drugs.

Papillary muscle sling: a new functional approach to mitral repair in patients with ischemic left ventricular dysfunction and functional mitral regurgitation.

BACKGROUND: In patients with ischemic left ventricular dysfunction (LVD) and functional mitral regurgitation (FMR), restoring a more normal alignment between mitral annulus and laterally displaced papillary muscles (PM) may be beneficial in terms of mitral repair and regional dynamics. METHODS: Ten patients, 29 to 78 years old, with an ejection fraction of 25% to 45%, pulmonary hypertension greater than 60, and New York Heart Association Class III-IV, had their PMs drawn together by a tightly encircling loop using a 4-mm Gore-Tex tube. Associated mitral annuloplasty rings were only moderately undersized. Efficiency was essentially evaluated on reversal of mitral tenting and control of FMR. RESULTS: Postoperative echocardioraphy revealed changes in "tenting effect" from 14 +/- 2.8 mm to 4 +/- 1.41 mm. Regurgitation is none to trivial in 9 patients, and mild in 1 patient. The posterior left ventricular wall between the PMs is shortened as a result of the surgical remodeling and may be beneficial on local dynamics. CONCLUSIONS: Joining the PM side-by-side has an obvious immediate effect on mitral leaflet mobility by suppressing the tethering due to displacement of the PM. An eventual result on local ventricular dynamics needs confirmation.