Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharma- cology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R

Applications of fluorescence and bioluminescence resonance energy transfer to drug discovery at G protein coupled receptors

The role of G protein coupled receptors (GPCRs) in numerous physiological processes that may be disrupted or modified in disease makes them key targets for the development of new therapeutic medicines. A wide variety of resonance energy transfer (RET) techniques such as fluorescence RET and bioluminescence RET have been developed in recent years to detect protein–protein interactions in living cells. Furthermore, these techniques are now being exploited to screen for novel compounds that activate or block GPCRs and to search for new, previously undiscovered signaling pathways activated by well-known pharmacologically classified drugs. The high resolution that can be achieved with these RET methods means that they are well suited to study both intramolecular conformational changes in response to ligand binding at the receptor level and intermolecular interactions involving protein translocation in subcellular compartments resulting from external stimuli. In this review we highlight the latest advances in these technologies to illustrate general principles

Playing-related musculoskeletal problems among professional orchestra musicians in Scotland: a prevalence study using a validated instrument, the Musculoskeletal Pain Intensity and Interference Questionnaire for Musicians (MPIIQM)

Many epidemiological surveys on playing-related musculoskeletal problems (PRMPs) have been carried out on professional musicians, but none have evaluated or confirmed the psychometric properties of the instruments that were used. The aim of the present study was to evaluate the prevalence of PRMPs among professional orchestra musicians and to gather information on pain intensity and pain interference on function and psychosocial variables, using a self-report instrument developed and validated specifically for a population of professional orchestra musicians. METHODS: Out of 183 professional orchestra players, 101 took part in the study (55% response rate) and completed the Musculoskeletal Pain Intensity and Interference Questionnaire for Musicians (MPIIQM). RESULTS: Lifetime prevalence of PRMPs was 77.2%, 1-year prevalence was 45.5%, and point prevalence was 36.6%. Of the PRMP group, 43% reported having pain in three or more locations, most commonly the right upper limb, neck, and left forearm and elbow. However, predominant sites of PRMPs varied between instrument groups. The mean pain intensity score for the PRMP group was 12.4±7.63 (out of 40). The mean pain interference score was 15.2±12.39 (out of 50), increasing significantly with the number of reported pain locations (F=3.009, p=0.044). CONCLUSION: This study confirms that musculoskeletal complaints are common in elite professional musicians and that the use of an operational definition and a validated self-report instrument allows for more accurate and meaningful estimates of pain prevalence.</jats:p