Enzyme inhibitor
These furanocembrenolide-class diterpenes (FWBipinnatin-A = 488.49 g/mol;
CAS (Bipinnatin A) = 99552-28-0; FWBipinnatin-B = 458.46 g/mol; CAS
(Bipinnatin B) = 99552-24-6; FWBipinnatin-C = 460.48 g/mol; CAS (Bipinnatin
C) = 123483-20-5), isolated from the bipinnate sea plume Antillogorgia
bipinnata, a sea fan found in the eastern Caribbean Sea, are naturally
occurring marine neurotoxins that irreversibly inhibit nicotinic acetylcholine
receptors by forming a covalent bond with Tyrosine-190 in the a-subunit
of the receptor (See also Lophotoxin). The parent species of the bipinnatins
display little, if any, affinity for the nicotinic receptor. Preincubation of the
toxins appeared to produce a single, relatively stable, active toxin species
that irreversibly inhibited the two acetylcholine-binding sites on the
nicotinic receptor with two distinguishable apparent pseudo first-order rates.
The difference in the rates of irreversible inhibition of the two binding sites
on the receptor was exploited to selectively inhibit one site for the
pharmacological investigation of the other. The bipinnatins preferentially
inhibited the binding site near the ad-subunit interface that displays low
affinity for metocurine and high affinity for acetylcholine. The bimolecular
reaction constants for the interaction of the bipinnatins with the nicotinic
receptor decreased in the order: Bipinnatin-B > Bipinnatin-A > Bipinnatin-
C, for both acetylcholine-binding sites. The ratio of the bimolecular reaction
constants for the two binding sites on the receptor was not the same for the
three bipinnatins, suggesting that the reaction of the bipinnatins with the
nicotinic receptor is sensitive to differences in the structure of the two
acetylcholine-binding sites.
