Benzimidazole CB2 agonists: design, synthesis and SAR.

A new series of CB2-selective agonists containing a benzimidazole core is reported. Design, synthesis, SAR and pharmacokinetic data for selected compounds are described.

Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy.

A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.

Decahydroquinoline amides as highly selective CB2 agonists: role of selectivity on in vivo efficacy in a rodent model of analgesia.

A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain.

Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead.

High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor-acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor K(i)=44nM and IC(50)=38nM.

Functional and pharmacological properties of canine ERG potassium channels.

We established HEK-293 cell lines that stably express functional canine ether-à-go-go-related gene (cERG) K(+) channels and examined their biophysical and pharmacological properties with whole cell patch clamp and (35)S-labeled MK-499 ([(35)S]MK-499) binding displacement. Functionally, cERG current had the hallmarks of cardiac delayed rectifier K(+) current (I(Kr)). Channel opening was time- and voltage dependent with threshold near -40 mV.

Dorsal horn-enriched genes identified by DNA microarray, in situ hybridization and immunohistochemistry.

Background: Neurons in the dorsal spinal cord play important roles in nociception and pain. These neurons receive input from peripheral sensory neurons and then transmit the signals to the brain, as well as receive and integrate descending control signals from the brain. Many molecules important for pain transmission have been demonstrated to be localized to the dorsal horn of the spinal cord.