Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na+ channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 – for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Cav1.1-Cav3.3, with even newer nomenclature α1A-α1I and α1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

Neuropathic pain is a kind of pain related with functional abnormality of neurons. Despite large progress in pharmacotherapy, neuropathic pain is still considered an unmet need. Nowadays, there are few drugs registered for this condition, such as pregabalin, gabapentin, duloxetine, carbamazepine, and lidocaine. Among them, pregabalin, gabapentin and carbamazepine are well known antiepileptic drugs. Among the group of new antiepileptic drugs, which are addressed to 1% of human world population suffering from seizures, it turned out that 30% of the seizures resistant to pharmacotherapy has not enough market to justify the costs of drug development. Therefore, it is already a phenomenon that researchers turn their projects toward a larger market, related with possible similar mechanism. Anticonvulsant mechanism of action is in the first place among primary indications for drugs revealing potential analgesic activity. Therefore, many drug candidates for epilepsy, still in preclinical stage, are being evaluated for activity in neuropathic pain. This review is focusing on antiepileptic drugs, which are evaluated for their analgesic activity in major tests related with neuropathic pain. Relation between structure, mechanism of action and result in tests such as the Chung model (spinal nerve ligation SNL), the Bennett model (chronic constriction injury of sciatic nerve CCI) and other tests are considered. The first examples are carbamazepine, gabapentin, and lacosamide as drugs well established in epilepsy market as well as drug candidates such as valnoctamide, and other valproic acid derivatives, novel biphenyl pyrazole derivatives, etc. Moreover, clinical efficacy related with listed animal models has been discussed.

No abstract

C h emIn fo rm 2 0 1 2 , 4 3 , issu e 1 0 © 2 0 1 2 Wiley -VCH Verl ag G m b H & Co. K G a A , We i n he i m Rece ptor bin ding activ ity X 0 280 DOI: 1 0.100 2/ch in.201 2102 20 Synthesis , α-Ad r en o c ep to r s A ffin ity an d α1-Ad r en o c ep to r An ta g o n istic Pro p e rt ies of Some 1,4-Substit uted Piperazine D eriva t iv es. -A se rie s of 1,4-s ubs titute d pipe r a zine de r iv ative s ( I) a r e synthe siz ed and eva luate d for a f finity towards α1 -an d α 2-re ce p t ors b y ra dioliga nd-bind ing a ssa y. Fu rthermore , α1-a ntagonistic propertie s a re che cke d for the most prom isin g co mpoun ds by m ean s o f p hen ylep hrine-ind uce d co ntr ac tion in isolate d r at a orta . The bes t pr ope rties are shown by (Ia ) w ith a Ki(α1) va lu e of 2.4 nM a nd a 142 fold be tte r s ele c tivity to α 1 ove r α 2-a drenoc ep tors. All m ost promisin g co mpoun ds posse ss a n 1-(o-me thoxyp hen yl)pipe r a zine moie ty. -(MARONA, H .; KU BA CK A, M.; FILIPEK , B.; SIWE K, A.; D YB AIA , M.; SZNE LER, E.; POCIE CHA, T.; GUNIA, A.; WASZ KIE LEWIC Z*, A. M.; Ph arma zie 66 (201 1) 10, 733-73 9, http ://dx.do i.org/10 .1691 /ph.20 11.1 543 ; Dep . B i oorg. Chem ., Fac . Pha rm ., J agie llonia n U niv. Me d. C oll., PL-30-688 K ra kow, Pol.; Eng.) -H. H abe r 10 -22 0

No abstract

A series of aminoalkanol and amino acid derivatives of trans-cinnamic acid as well as aminoalkanol derivatives of -phenylcinnamic acid was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (ScMet) induced seizures as well as neurotoxicity assessment. Six of them showed protection in MES at 100 mg/kg b.w. and one at 300 mg/kg b.w. For selected derivatives evaluation in ScMet test in rats after per os (p.o.) administration, 6-Hz test in mice and pilocarpine-induced status in rats were performed. The results are quite encouraging and further modification of the structures might lead to discovering new potential anticonvulsants.

The chemiluminescence of stimulated cells with phorbol myristate acetate and the production of nitric oxide after stimulation with lipopolisaccharide in the presence of the parent compounds FAA (flavone-8-acetic acid = (4-oxo-2-phenyl-4H-chromen-8-yl)acetic acid), XAA (xanthone-4-acetic acid = (9-oxo-9H-xanthen-4-yl)acetic acid), and appropriate xanthone derivatives (1-7) was determined. Also the toxicity of the FAA, MFAA ((6-methyl-4-oxo-2-aryl-4H-chromen-8-yl)acetic acid), XAA and 1-7 against J-774A.1 cultured cells was evaluated. Compound 5 (2-methyl-2-{[(9-oxo-9H-xanthen-2-yl)methyl]sulfanyl}-propanoic acid) was effective in inhibiting chemiluminescence of J-774A.1 cells but most of the other tested compounds stimulated the reaction. FAA and two xanthones with a methoxycarbonyl moeity slightly decreased the generation of nitric oxide at 50 μM. Most of the tested compounds (1-7) showed weak toxicity at concentration of 100 μM.