1 This study describes the pharmacological comparison of the muscarinic partial agonists sabcomeline, xanomeline and milameline at human cloned muscarinic receptor subtypes (hM 1 ± 5 ). 2 Radioligand binding studies at the hM 1 ± 5 muscarinic receptor subtypes were compared with functional studies using microphysiometry using carbachol as the standard full agonist. 3 In binding assays none of the compounds studied displayed preferential a nity for the M 1,3,4 or M 5 subtypes although carbachol was less potent at hM 1 than hM 3,4,5 . 4 In functional studies, all of the compounds studied displayed similar levels of e cacy across the muscarinic receptors with the exception of M 3 , where there was a large apparent receptor reserve and the compounds behaved essentially as full agonists. 5 Sabcomeline was the most potent agonist in functional studies but also showed the lowest e cacy. In terms of potency, xanomeline showed some selectivity for M 1 over M 2 receptors and milameline showed some selectivity for M 2 over M 1 receptors. 6 These results show the value of microphysiometry in being able to compare receptor pharmacology across subtypes irrespective of the signal transduction pathway. 7 None of the partial agonists showed functional selectivity for M 1 receptors, or indeed any muscarinic receptor, in the present study.

The aim of this study was to characterize the pharmacological profile of the GABAB1/GABAB2 heterodimeric receptor expressed in Chinese hamster ovary (CHO) cells. We have compared receptor binding affinity and functional activity for a series of agonists and antagonists. The chimeric G‐protein, Gqi5, was used to couple receptor activation to increases in intracellular calcium for functional studies on the Fluorimetric Imaging Plate Reader (FLIPR), using a stable GABAB1/GABAB2/Gqi5 CHO cell line. [3H]‐CGP‐54626 was used in radioligand binding studies in membranes prepared from the same cell line. The pharmacological profile of the recombinant GABAB1/B2 receptor was consistent with that of native GABAB receptors in that it was activated by GABA and baclofen and inhibited by CGP‐54626A and SCH 50911. Unlike native receptors, the GABAB1/GABAB2/Gqi5 response was not inhibited by high microMolar concentration of phaclofen, saclofen or CGP 35348. This raises the possibility that the GABAB1/GABAB2/Gqi5 recombinant receptor may represent the previously described GABAB receptor subtype which is relatively resistant to inhibition by phaclofen. British Journal of Pharmacology (2000) 131, 1050–1054; doi:

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The effects of SB 206284A, 1-[7-(4-benzyloxyphenoxy)heptyl] piperidine hydrochloride, have been investigated in vitro on calcium and sodium currents in rat-cultured dorsal root ganglion (DRG) neurones and potassium-mediated calcium influx in rat synaptosomes. Cardiovascular hemodynamic effects in both anesthetized and conscious rats, and neuroprotective activity in in vivo cerebral ischemia models were also investigated. In the rat DRG cells, SB 206284A caused almost complete block of the sustained inward Ca2+ current (IC50 = 2.4 microM), suggesting that the compound is an effective blocker of slowly inactivating, high-voltage calcium current. SB 206284A reduced locomotor hyperactivity in the gerbil bilateral carotid artery occlusion model without affecting ischemia-induced damage in the hippocampal CA1 region. In the rat middle cerebral artery occlusion model, SB 206284A reduced lesion volume in the posterior forebrain, and in the rat photochemical cortical lesion model, lesion volume was reduced even when treatment was delayed until 4 hours after occlusion. At neuroprotective doses, SB 206284A had no cardiovascular effects. These findings show that SB 206284A is a novel calcium channel antagonist that shows neuroprotective properties.