Recent advances in marine pharmacology

TIPS - March.

1980

IX7 Debromoaply+iatoNin blue-green

marine

latoriaceac)

New York, pp. 129-t72. KrnjeviL K. (1974) Physrol. Rev. 54, JtR-5JO. Nastuk. W. 1.. (1953)F& /+x. 12. 102. Ryall. R. W. and Kelly. J. S. (cds) (1978) lonfophoresrs and Transmiiter Mechanisms m the Mwnmalian C’enfral Nervous Sytrem, Elsevier/Norlh-Holland Amsterdam and WCH York.

isolated tram the

alga f..vnnh,,a (O~CII-

and

fror,l

a

\ea

hare

(Stylocheilus lon~~caudai that feed\ on II, has antileukemic acti\tt!. in mice and i\

also dermonecrolic”. Dr Server .V. h’orhechkm 1.5a tenror rewarch worker m the Laboratory OJ Nrurn;~harmacn/o~_~O/ rh,In.rtrfutc u/ PhormocnloR.v m the Arademv 01 Mrdtcal kiencer oJ rhr ti S. F R Smce 1966 he hrrc been CnRG?ed m rewarch on fhe pharmacntoyy of cenrral c_vnclprrr wanwn,won.

Recent advances in marine pharmacology

Other compounds with antitumor activity are in various stages of development. SO far. hcweter. c>to\ine arabinoride (araC) remains the onlk clinically useful anticancer agent ~5hose origin can be traced to a marine natural product. It was synthesized using as models arabinosyl thymine (Sponpothymidine) and arabinosyl uracil (Spongouridine) chance crypta.

from

originally the

Since Faulkner: antibiotic5

from

isolated

sponge

ha\ recenti! marine

b)

Cr_vprorerh.va rcbiewed

organism\

thal

subject will not be considered here.

Frederick A. Fuhrman

Marine toxins Poisonous marine organism\ hake proved to be a valuable source of di\cr,c

From

the

organisms,

great

diversity

of

marine

it might be expected that new

chemical compounds with useful pharmacological actions could be isolated from them.

Indeed,

the -hemistry

of marine

natural products is being actively pursued in

many

world.

laborator,es

throughout

the

It is the subject of a currer t series

of

algal

extracts

comparison,

the

are

average

extracts of terrestrial

active.

In

activity

of

plants is about 3wo.

Cytotoxic compounds tend to occur tropical rather than temI?orate species.

in

At the University of I-California, Santa Barbara, Robert Jacobi; and associates are using blockade of ~11 division in sea

of symposia of the International Union of Pure and Applied Chemistry and of

urchin eggs for screenin: naturally occurring compounds from alarine organisms.

several recent books, especially the series

Several compounds block cell division in this system by interfering with formation of microtubules.

edited by Scheuler”. !n contrast, the pharhas macologv of these compounds received much less attention, even though many of the bioactive

compounds

novel chemical structure certainly would never synthesized in any rational designing

new

drugs.

are of

Among the cornpour& antiturr.or

activity

with significant

in several systems are

of

Pharmacology

American

been responsible for sporadic human fatalities uhen eaten. Surugatoxin is an unusual combination oi h-bromoindols, pteridine and myoincsitol. It ha\ a powerful ganglionis blol:king a&on zome 11 times that of trtraethylammonium chloride. The most toxic non-protein

of the genus Pai&rhou.

for

-The LD.,

palytoxin has a molecular #sighr of abour 3000 and rhe slru ksr 10 bz determined. Pallto\in I\ d lo4 irritant and animals giben lethal don\

Thera-

peutics. The papers presented there will be

to habe renal fadurc.

published in Federarion

heart fallurs and gensrahrrd

Proceedings

and

some of the work described will be mentioned here without specific citation. or

Screening for these activities has been

in several laboratories for many years. In assays of cytotoxicity against human carcinoma (KB) cells. some Q-12% of extracts of marine animals are active, while only about 2% carried

out

has been

reported to be as IOU as 0.015 ~g hp i.~ in rabbits. .L\lthough clearI> noI a protein.

recent

Oregon Society for

and Experimental

Compounds with antimicrobial cytotoxic activity

compound

program Some

the Portland,

the

Yosbiro Hashimoto’. Among the toxin\ that have received pharmacological srudh is rurugatosin from the itor> shell gastropod Eab_vlonia japorricu. \\hish ha\

from marine organipms is pal! royin from several species of zoanthid (Corlenrsrnta)

macology were presented last August in a meeting

monograph by one of the leading m\esrlgators in the field, the late Professor

that almost have been

examples of current work in marine phar-

symposittm at

bioacti&e compounds. Much of rhic Polk has just been summarized m a useiul

some derivatives of cembrene (1). a group of compounds so far found in marine organisms only in subclass Octocorallia: gonocea)

and

the soelentcrate the sea-fans (Gor-

the soft

corals

(Alcyon-

tion

important

mecham,m

Such an effect ma\ tion of Ca”

from

the soft

of the genus Eunicea.

palytoxin

musslr

contraction. has

been

Thi\

demon-

Sirntluriu

strated to occur in strips of ventricle and

gorgonians

of rabbit aorta. One of the first marine toxins tu br .. bt v.L:<,.. .- H., ,” il ..l:(il I r

coral from

action.

result from stimula-

action

of

a\ 112

oi

inf.uu into smooth

several species of the sea fan Pkwura, and asperdial


and rhis ha% been propo4

most

cells, and consequent

sinularin

NUTS found

diathcsls. In perfused heart> the town produces marked coronary \a~c’ons~rlc‘-

acea). These include crassin acetate from

flexibi/is

ihozh.

when thl: Nu + channel is open. The action is irreversible. Anthopleurin A has a similar action. l’hesc polypeptide toxins also WI on mammalian heart muscle in low concentrations (I-S x IO u M). ATX-I1 has a dose-dependent positive intropic cffecc on isol,ated mammalian hearts at concentrations of 2-100 ,nkt and various cardiotoxic effects at slightly higher concentrations. The action of AP-A on the heart has been well investigated”. It has a powerful positive inotropic action with almost no chronotropic rffect in a variety of isolated heart preparations. in cats and dogs the effect is primarily cardiotonic, with little effect on arterial pressure. As would be expected, .AP-A is antigenic and not effective orally. telrodotosin (11, in~.e,tigared \t as orlgrndil!: isolated tram the puffer fish and. nou, known to (Tetraodomidae). in neMIs (Salamandridae), an gob>-, ,roplzal frog\ (Afdopus~.

OLCliF

orienta!

and the
escirarlon,

and

F

thus

a

local

anesrhetlt rome 10,000 times more poter:t

Ihan

procaine.

Saxitoxin

(Ill),

the

.HtU

frog A relopus chiriquiensis. Chiriquirosin, which retains the full pharmacological act:vity, differs from tetrodotoxin only in that an unidentified group with a mass of 104 replaces the -CH,OH group at C-6. Recent evidence obtained by C. Y. Kao and associates indicates that chiriquitoxin and tetrodotoxin bind to the same membrane receptor, but that chiriquitoxin interferes to some extent (20%) with the K- channel as well as the s.odium channel. One implication of this finding is that the Na’ channel receptor, rather than being located within the channel, is on the outer surface or the membrane. Also, since the maximum distance from the quanidinium group of ~zhiriquitoxin IO the still to be defined group on C-6 is 1.5 nm at least some K + channels must be within this distance of Na * channels. Polypeptides from sea anemones

sheIll& poison, from dinofiagellares of the genus Gonyauiax, has essentially the same pharmacological action. Although ihey are too toxic and too readily diffusible to be iuseful in medicine. these toxins have proved to be exceedingly powerful tools in physiological and pharmacological research. At least iix orher loxinK ciosely related ~.hrmically to savitoxin habe been &srit%d in Gorr_vaulax by Shimizu and aswciates a! the Uniwrsir:; of Rhode Isia:ld. and those rhat hase been studied have essentially the same biological action as saxitoxin itself. In contrast, chemical modification of tetrodotoxin has almost invariably resulted in loss of biological actiirty, and only one naturatly occurring analog is known -chiriquitoxin from the paralytic

In has been known for a decade that a polypeptide from the Bermuda anemone, C.and~&~ctis gigonreu, greatly prolongs the closing (inactivation) of Na- channels in crustacean (but not squid) axons. These, and other, effects can now be associated with specific polypeptides from several coelenterates. Biress’ 7.nd co-workers in West Germany isolated three polypeptidc toxins from Anemonia sulcara and foul from Condylactis auranticu. Norton’ anlc associates in Hawaii isolated two from Anthopleuro xanthogrammica and one from .4. eleguntissimo. The molecular weights range from 2878 to 5630 and the amino acid sequences of mast of them are known. They are homologous to a high degree. Toxin Ii from A. sulco~~ (ATX-II) is primarily a neurotoxin like Condyluctis Toxin. It binds to the membrane only

Miscebneous

compounds

Methylaplysinopsin (1V) is a tryptophan derivative isolated from the sponge Apl.vsrnopsis rericu!atu at the Roche Me

t-l

IV Research Institute of Marine PharmaIt has antico1oe.y in Australia”‘. depressant effects in mammals and was shown to be a short-acting inhibitor of especially with monoamine oxidase, serotonin as substrate. Neurochemical and neurophysiological evidence indicates that it potentiates central serotonergic neurotransmission. The Roche group have also isolated from a red alga a halogenated monoterpme, plocamadiene A (V). A large num.ber of other monoterpenes as well as diterpenes from marine algae have weak depressant effects on the central nervous system of mammals. Plocamadiene A, hoNever, produces an unusual longlasting reversible spastic paresis in mice that may serve as a possible experimental model of spasticity. A novel hybrid molecule. autonomium, was obtained from the sponge Verongio

iXY

Heading list

fistuluris by investigators at the University

tions. Doridosine

of Oklahoma.

adenosine and most of its derivatives in that it is not mactibated ly adeno\inc

The compound

phenethylene

moiety

and

includes a

a quaternary

ammonium group. Kaul and co-workers found that it produces a transient pressor response

followed

by a fall

in arterial

Is2

however,

from

Jeaminase and thus produces bradycardia and hypotension that last for hours in mammals. Doridosine appears to prolong the action of pentobarbital and to reduce body temperature, but it is not known

pressure in mammals.

Cl ‘,

differs,

n

whether these effects are the result of a direct action on the central nerhou5

&

system or are a consequence

of severe

hypotension. The same compound has been isolated from the sponge Tedaniu b> the Roche group who state that it also hat. muscle relaxant, anti-inflammatory anti-allergic properties.

and

V The Oklahoma

group’ have found that

severai

halogenated

marine

algae

cyclic

potentiate

effect of pentobarbital.

ethers

from

the depressant The most potent,

dactylyne (VI) from the sea hare, Apf.vsiu dactylornela was shown to inhibit the metabolism of pentobarbital.

Origins of the receptor theory John Parascandolaz

VI We’

recently

riboside. sine)

In

isolated

a new

I-methylisoguanoslne

from

the

digestive

nudibranch Anisodoris

(dorido-

gland

nobik

purine of

the

Like other

adenosine derivatives, doridosine has marked negative inotropic and chronotropic effects on isolated

heart prepara-

the

inaugural

Pharmacological Cuthbert

issue of

‘Trett&

Sciences’,

A

in \V .

described the last two decades in

ptiarmaca”-‘. art~&s

Te\rbook.

2nd

ret I~U

often
that

the receptor theory dates baih to the irorh

pharmacology

as “the age of the rzcep-

of Paul

tar”’

J. Ariens

Newport Langlc!; (18X!-1925t’-’ n in the early twentirrh century. but generally do not pro\ ide much more information than

and E.

noted

that

for

decades the receptor concept has been “indi$pensable for discussing and underof of action standing the mode

Ehrlich

(IYM-1915)’

and John

that about the origins of the concept. The