Katalin Tarczy-Hornoch

Characterization of the binding of omega-conopeptides to different classes of non-L-type neuronal calcium channels

The interaction of two synthetic omega-conopeptides SNX-111 (MVIIA) and SNX-230 (MVIIC) both derived from the marine snail Conus magus, with non-L-type neuronal voltage-sensitive calcium channels (VSCC) in rat brain synaptosomal preparations has been investigated with the aid of well-characterized 125I derivatives of the two peptides. To assess the effects of iodination on the binding characteristics of SNX-111 and SNX-230, the corresponding peptides containing monoiodotyrosine in place of tyrosine, namely, SNX-259 ([127I]SNX-111) and SNX-260 ([127I]SNX-230), respectively, were prepared by solid-phase synthesis. Saturation analysis showed that [125I]SNX-111 and [125I]SNX-230 bound to two distinct classes of high-affinity sites with apparent Kds of 9 and 11 pM and Bmaxs of 0.54 and 2.2 pmol/mg protein, respectively. Kinetic analysis revealed that both peptides exhibited high association rates as well as rapid dissociation rates in contrast to the 125I derivative of the synthetic omega-conopeptide from Conus geographus, GVIA (SNX-124), which binds irreversibly to N-type channels in rat brain synaptosomes. Competition binding experiments with [125I]SNX-111 and [125I]SNX-124 established that both of them bind to the same site, namely, N-type VSCC. The site detected by the binding of [125I]SNX-230 is distinct from N-type VSCC since SNX-111 has very low affinity (K(i) = 135 nM) in competition studies. Recent findings that a novel high-voltage-activated calcium channel in rat cerebellar granule neurons is resistant to blockers of L-, N-, and P-type VSCC but is highly sensitive to SNX-230 suggest that the [125I]SNX-230 binding site may represent this novel type of calcium channel or another, as yet undescribed, VSCC.

Multiple parallel synthesis of N, N-dialkyldipeptidylamines as N-type calcium channel blockers

Selective N-type Voltage Sensitive Calcium Channel (VSCC) blockers have shown utility in several models of stroke and pain. A series of N,N-dialkyldipeptidylamines with potent functional activity at N-type VSCCs has been identified. Multiple parallel synthesis of a focused array of thirty compounds using polymer-supported quenching reagents and preliminary pharmacology are presented. Eighteen compounds were identified with an IC50 below 1 microM in an in vitro functional assay.

Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers.

Voltage activated calcium channel (VACC) blockers have been demonstrated to have utility in the treatment of stroke and pain. A series of aminomethyl substituted phenol derivatives has been identified with good functional activity and selectivity for N-type VACCs over sodium and potassium channels. The methods of synthesis and preliminary pharmacology are discussed herein.

Synthesis and structure-activity relationship of substituted 1,2,3,4-tetrahydroisoquinolines as N-type calcium channel blockers

Voltage Activated Calcium Channel (VACC) blockers have been demonstrated to have utility in the treatment of pain and stroke. A series of aminomethyl substituted isoquinolinol derivatives with potent functional activity for N-type VACCs have been identified. Their synthesis and preliminary pharmacology are discussed herein.