Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1.

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.

Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor.

Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), which has now entered clinical trials.

TRPV1 antagonist, SB-366791, inhibits glutamatergic synaptic transmission in rat spinal dorsal horn following peripheral inflammation.

The anti-hyperalgesic effects of TRPV1 receptor antagonists are well documented in animal models of pain, however, the precise site of their action is not known. Here we have examined the effects of the selective TRPV1 antagonist SB-366791 on glutamatergic synaptic transmission in substantia gelatinosa using spinal cord slices from either control rats or animals that had undergone a peripheral inflammation induced by intraplantar injection of Freund's complete adjuvant (FCA). In control animals, SB-366791 (30 microM) had no effect on spontaneous excitatory post-synaptic currents (sEPSC) or evoked EPSCs.

Inhibition of Ih reduces epileptiform activity in rodent hippocampal slices.

Hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels regulate membrane potential, neurotransmitter release, and patterning of synchronized neuronal activity. Currently, there is an intense debate as to whether or not these ion channels play a pro- or anticonvulsant role in vivo. To gain an insight into this question, we have examined how inhibitors of the response mediated by HCN channels (referred to as I(h)) affect epileptiform activity induced in adult hippocampal slices.

Activation of SK channels inhibits epileptiform bursting in hippocampal CA3 neurons.

The role of calcium-activated potassium channels in the regulation of neuronal hyperexcitability, as in epilepsy, is unclear. To examine this issue, we have used the acute hippocampal slice model of epileptiform activity to investigate the effects of an enhancer of SK channel activity, 1-ethyl-benzimidazolinone (EBIO). That EBIO is an SK channel modulator was confirmed by its potentiation of hSK1, hSK2, hSK3 and hIK currents (EC(50) values in the range of 130-870 microM) and its apamin (1 microM) sensitive reduction of the number of action potentials fired in CA3 pyramidal neurons in response to a depolarizing current step.