Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T

Malmberg, Annika B.; Gilbert, Heather; McCabe, R. Tyler; Basbaum, Allan I.

doi:10.1016/s0304-3959(02)00303-2

Cited by 127 publications

(92 citation statements)

References 55 publications

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“…In support of this notion, spinal administration of NR2B antagonist ifenprodil or Ro 25-6981 produced potent antinociception and inhibited LTP in spinal dorsal horn in neuropathic pain model. 26,67 Although spinal NMDA receptors have received a great deal of attention, evidence is accumulating that NMDA receptors located in supraspinal structures, such as brain stem, play an important role in chronic pain. Upregulation of mRNAs encoding NMDA receptor subunits, such as NR1, NR2A, and NR2B, has been observed in the RVM after inflammation.…”

Section: Function In Chronic Painmentioning

confidence: 99%

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

2009

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Summary:Neuropathic pain is generally defined as a chronic pain state resulting from peripheral or central nerve injury, or both. An effective treatment for neuropathic pain is still lacking. The NMDA receptor, one type of the ionotropic glutamate receptors, is known to be important for triggering long-lasting changes in synapses. NMDA receptor-dependent synaptic plasticity plays roles not only in physiological functions such as learning and memory, but also in unwanted pathological conditions such as chronic pain. This review addresses recent progress on NMDA receptors in neuropathic pain, with particular emphasis on the NR2B-subunitcontaining receptors. The expression and function of NMDA receptors in synaptic plasticity in the pain transmission pathway from dorsal root ganglia to the anterior cingulate cortex is reviewed, and preclinical and clinical investigations of selective NMDA receptor in neuropathic pain are discussed. The NMDA receptors, in particular NR2B-containing NMDA receptors, serve as promising targets for treatment of neuropathic pain.

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Section: Function In Chronic Painmentioning

confidence: 99%

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

2009

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“…These peptides are effective weapons for survival of the snails, and are also emerging as neurotherapeutic drugs (Alonso et al, 2003;Malmberg et al, 2003). The majority of the conotoxins are built from small superfamilies of disulfide bond-containing structural scaffolds.…”

Section: Introductionmentioning

confidence: 99%

Subtype-selective antagonism of N-methyl-d-aspartate receptor ion channels by synthetic conantokin peptides

2007

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Conantokin-G (con-G), conantokin-T (con-T), a truncated conantokin-R (con-R [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]), that functions the same as wild-type con-R, and variant sequences of con-T, were chemically synthesized and employed to investigate their selectivities as antagonists of glutamate/glycineevoked ion currents in human embryonic kidney-293 cells expressing various combinations of NMDA receptor (NMDAR) subunits (NR), viz., NR1a/2A, NR1a/2B, NR1b/2A and NR1b/2B. Con-G did not substantially affect ion flow into NR1a,b/NR2A-transfected cells, but potently inhibited cells expressing NR1a,b/NR2B, showing high NR2B selectivity. Con-T and con-R served as nonselective antagonists of all of four NMDAR subunit combinations. C-terminal truncation variants of the 21-residue con-T were synthesized and examined in this regard. While NMDAR ion channel antagonist activity, and the ability to adopt the Ca 2+ -induced α-helical conformation, diminished as a function of shortening the COOH-terminus of con-T, NMDAR subtype selectivity was enhanced in the con-T[1-11], con-T[1-9], and con-T[1-8] variants toward NR2A, NR1b, and NR1b/2A, respectively. Receptor subtype selectivity was also obtained with Met-8 sequence variants of con-T. Con-T[M8A] and con-T[M8Q] displayed selectivity with NR2B-containing subunits, while con-T[M8E] showed enhanced activity toward NR1b-containing NMDAR subtypes. Of those studied, the most highly selective variant was con-T[M8I], which showed maximal NMDAR ion channel antagonism activity toward the NR1a/2A subtype. These studies demonstrate that it is possible to engineer NMDAR subtype antagonist specificity into con-T. Since the subunit composition of the NMDAR varies temporally and spatially in developing brain and in various disease states, conantokins with high subtype selectivities are potentially valuable drugs that may be used at specific stages of disease and in selected regions of the brain.

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“…after ischemic stroke) (9 -11), pain (12)(13)(14), epilepsy (3,6,7,15), and probing mechanisms of drug addiction (16). Con-G (CGX-1007, Cognetix, Inc.) has reached phase I clinical trials for both pain and epilepsy (14).…”

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confidence: 99%