The shortcoming of using glibenclamide in exploratory clinical headache provocation studies.

Objective: Preclinical and clinical studies implicate the vascular ATP-sensitive potassium (K) channel in the signaling cascades underlying headache and migraine. However, attempts to demonstrate that the K channel inhibitor glibenclamide would attenuate triggered headache in healthy volunteers have proven unsuccessful. It is questionable, however, whether target engagement was achieved in these clinical studies.

Pharmacological Profiling of K Channel Modulators: An Outlook for New Treatment Opportunities for Migraine.

Migraine is a highly disabling pain disorder with huge socioeconomic and personal costs. It is genetically heterogenous leading to variability in response to current treatments and frequent lack of response. Thus, new treatment strategies are needed.

Anti-Tremor Action of Subtype Selective Positive Allosteric Modulators of GABA Receptors in a Rat Model of Essential Tremors.

Essential tremor (ET) is among the most prevalent neurological disorders and the most common cause of abnormal tremors. It is characterized by postural and action tremors ranging from 4 to 12 Hz. The treatments of choice for ET are propranolol and primidone, but their use is associated with adverse effects like hypotension, depression, and cognitive impairments.

Expression of α3β2β4 nicotinic acetylcholine receptors by rat adrenal chromaffin cells determined using novel conopeptide antagonists.

Adrenal chromaffin cells release neurotransmitters in response to stress and may be involved in conditions such as post-traumatic stress and anxiety disorders. Neurotransmitter release is triggered, in part, by activation of nicotinic acetylcholine receptors (nAChRs). However, despite decades of use as a model system for studying exocytosis, the nAChR subtypes involved have not been pharmacologically identified.

Characterization of AN6001, a positive allosteric modulator of α6β2-containing nicotinic acetylcholine receptors.

α6β2-Containing nicotinic acetylcholine receptors (α6β2* nAChRs) are predominantly expressed in midbrain dopaminergic neurons, including substantia nigra pars compacta (SNc) neurons and their projections to striatal regions, where they regulate dopamine release and nigrostriatal activity. It is well established that nAChR agonists exert protection against dopaminergic neurotoxicity in cellular assays and parkinsonian animal models. Historically, drug development in the nAChR field has been mostly focused on development of selective agonists and positive allosteric modulators (PAMs) for the predominant neuronal nAChRs, α7 and α4β2.