US EPA

7429866 

Journal Article 

Actions of decarbamoyloxysaxitoxin and decarbamoylneosaxitoxin on the frog skeletal muscle fiber 

Yang, L; Kao, CY; Oshima, Y; , 

1992 

1 

Toxicon
ISSN: 0041-0101
EISSN: 1879-3150 

PERGAMON-ELSEVIER SCIENCE LTD 

OXFORD 

30 

5-6 

645-652 

English 

1325688 

10.1016/0041-0101(92)90858-3 

WOS:A1992JD01900010 

https://linkinghub.elsevier.com/retrieve/pii/0041010192908583
Exit
 

Two new analogues of the decarbamoyl series of paralytic shellfish toxins have been isolated through improved HPLC methods. In decarbamoyloxysaxitoxin (doSTX), the -OH function at C-13 of decarbamoylsaxitoxin (dcSTX) is changed to -CH3. In decarbamoylneosaxitoxin (dcneoSTX), the carbomyl side-chain of neosaxitoxin (neoSTX) has been removed. The new analogues were assayed on voltage-clamped frog skeletal muscle fiber for their potency in reducing the sodium current. Compared with neoSTX, the relative potencies of dcneoSTX are: 0.003 (at pH 6.50), 0.004 (pH 7.25), and 0.005 (pH 8.25). The influence of pH on the potency is the same in neoSTX and dcneoSTX. The fractional loss of potency caused by decarbamoylation is much greater in neoSTX than in STX, possibly because of an intramolecular interaction between the N-1 -OH in neoSTX and the -OH on C-13. Compared with STX, the ED50 for reducing INa by doSTX is 618 nM, making its relative potency 0.008 that of STX. Energetically, the decreased potency can be accounted for by the loss of two hydrogen bonds, one at the C-13 -OH of dcSTX, and the other at the amino group in the carbamoyl function of STX. These two groups resemble the C-6 and C-11 -OHs in tetrodotoxin, and probably bind to the same site-points. Thus, the near-identical actions of STX and TTX can be attributed to the common sharing of one ion-pair site and four hydrogen-bonding sites. If glutamate 387 of rat brain sodium channel II were the anionic site which ion-pairs with the 7, 8, 9 guanidinium of STX, then the carbonyl oxygen of asparagin 388 is the hydrogen-acceptor for the C-12 gem-diols. 

decarbamoylneosaxitoxin; decarbamoylsaxitoxin; saxitoxin; sodium channel; unclassified drug; decarbamoyloxysaxitoxin; drug derivative; saxitoxin; animal tissue; article; frog; muscle cell; nonhuman; structure activity relation; voltage clamp; animal; dose response; drug effect; in vitro study; muscle; sodium channel; Animalia; Anura; Animal; Dose-Response Relationship, Drug; In Vitro; Muscles; Rana temporaria; Saxitoxin; Sodium Channels; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.