Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors.

We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (~120-fold) and L-type (~3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.

A preclinical assessment of d.l-govadine as a potential antipsychotic and cognitive enhancer.

Tetrahydroprotoberberines (THPBs) are compounds derived from traditional Chinese medicine and increasing preclinical evidence suggests efficacy in treatment of a wide range of symptoms observed in schizophrenia. A receptor-binding profile of the THPB, d.l-govadine (d.

Evolving therapeutic indications for N-type calcium channel blockers: from chronic pain to alcohol abuse.

Clinical exploitation of the therapeutic potential of calcium channels has long been limited to L-type blockers for cardiovascular diseases. Recently, N-type blockers have been fully validated for the treatment of chronic pain, following approval of the intrathecally active ziconotide (Prialt(®)). This review describes the successful efforts to broaden the therapeutic scope of this mechanism to other major CNS indications, based on the discovery of N-type blockers orally active against pain.

A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain.

Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.

Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors.

A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC(50) values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.

Scaffold-based design and synthesis of potent N-type calcium channel blockers.

The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type calcium channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels.

A fluorescence-based high-throughput screening assay for the identification of T-type calcium channel blockers.

T-type voltage-gated Ca(2+) channels have been implicated in contributing to a broad variety of human disorders, including pain, epilepsy, sleep disturbances, cardiac arrhythmias, and certain types of cancer. However, potent and selective T-type Ca(2+) channel modulators are not yet available for clinical use. This may in part be due to their unique biophysical properties that have delayed the development of high-throughput screening (HTS) assays for identifying blockers.

Block of voltage-gated calcium channels stimulates dopamine efflux in rat mesocorticolimbic system.

Dopamine (DA) efflux from terminals of the mesocorticolimbic system is linked to incentive motivation, drug dependency and schizophrenia. Strategies for modulating dopaminergic activity have focused on transmitter receptors or the DA transporter, not on DA release, largely due to lack of systemically available drugs acting at this level. Central synapses use two main calcium channels for excitation-secretion coupling, either P/Q-type, N-type, or both.

A blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place preference, self-administration, and reinstatement.

There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication.

Linking calcium-channel isoforms to potential therapies.

Voltage-gated calcium channels underlie a plethora of physiological functions in the cardiovascular and nervous systems. Calcium channels are considered important targets for the treatment of conditions such as absence epilepsy and hypertension, and significant efforts are increasing to discover novel calcium-channel modulators for the treatment of pain. An overview of advances in the development of calcium-channel therapeutics in the areas of pain, epilepsy and disorders associated with cardiovascular function are discussed.