Absolute configuration and biological activity of viminol stereoisomers

Pharmacological

Research

Communications,

Vol. 8, No. 2, 1976

111

ABSOLUTECONFIGURATIONAND BIOLOGICAL ACTIVITY OF VIMINOL STEREOISOMERS ' D. Della ZAMBONS.p.A. Received

In

15September

the

a novel

last

with

robenzyl-pyrryl on the other

G. Benelli

and A. Sassi

Research Laboratories,

Bresso-Milan,

Italy

1975

few years our interest

compound (Fig.

derivative

Bella,

the group

(Teotino

1)

has been concentrated

which may be considered

ethanol

chain bearing,

on one and Della

side, Bella,

a pyrrylethanolamine

as substituents,

and

the

on viminol,

the o-chlo-

di-sec.butylaminic

1967; Teotino

et al.,

group

1972).

CH I 3

,

0

\

EHoHmCH-N2tiH-C2H5 2

N I

FiPure 1 - Molecular structure of viminol: -2-yl]-2-di-sec.butylamino-ethanol. I+:\ = asymmetric center) In et

al.,

previous 1973;

&j-C

l-Cl-(2-chlorobenzyl)-pyrrol-

experiments

we demonstrated

Della

and Lualdi,

Bella

H 2.5

both in animals (Della

1974)

and

Bella

in humans (Buzzelli

0) Paper presented by D. Della Bella at the Satellite Symposium on Acute Effects of Narcotic Analgesics (VI Internat. Congress of Pharmacology), Nokkala-Helsinki, July 18-20, 1975.

112

Pharmacological

et

al.,

Frigerio,

1970;

Monafo,

1971) that

however

in

quite

contrast

different,

the

the

test

of

in

set

known

all

of motility

adone

characterized

the

motor

In rats,

morphine,

to

after

is

admin-

methadone and viminol.

rats

viminol

adopting

has been shown

by morphine and meth-

a very marked ipermotility:

response

is

by using different

in naive rats

treated

properties:

liability.

and Davis (1967) it

in chronically

and

compounds viminol

obtained

is presented

by

analgesic

animal “species.

the compounds tested:

elicited

appear

different

Vol. 8, MO. 2, 1976

1970; Martinetti

narcotic

by the results

up by Babbini

The responses

conditions

most

is supported

the same pattern

istration

et al.,

possesses marked central

to

approaches

motility

that

Communications,

showing only a very poor addiction

This conclusion experimental

Martinetti

1974;

viminol

Research

in the same

absent (Babbini

et al.,

1973). Furthermore, narcotic jumping the

it

is

analgesics, behaviour

stronger

to pentazocine

wellknown the

(Saelens

that

challenge et

al.,

in

with

mice repeatedly naloxone

1971).

and propoxyphene,

compounds, the response to viminol

is shown in Table 1

animals.

which are, as wellknown, is even less

with

produces the typical

As it

is provoked in morphinized

response

treated

(Della

In comparison

poorly

Bella

addicting

and Lualdi,

1974). Table 1 - Jumping test

DRUGS

(Saelens et al.,

Total dose mg/kg i.p.

1971):

Z-day test

NALOXONE (100

results.

mg/kg i.p.) INCIDENCE

No. mice jumped/No.tested

CHALLENGE percentage

Viminol

1%

IO/73

13.7

Morphine

400

83/85

97.7

Pentazocine

170

6/20

30

d-Propoxyphene

114

7/36

19.5

Pharmacological The

Research

results

suppression

obtained

procedure

and subcutaneous

signs

appear not

clearly

monkeys

illustrated

administration

unchanged

substitute

Table

Vol. 8, No. 2, 1976

in morphinized

are

oral

does

Communications,

for

2 - Single

adopting

the

in Table

of viminol,

or even more

113

severe.

single

dose

2: following

the

14-hour

The conclusion

both

withdrawal

is

that

viminol

morphine. dose

suppression

test"

NUMBEROF MONKEYS

in morphinized

monkeys.

14-HOUR WITHDRAWAL SIGNS

FROM

I unchanged unchanged more severe more severe more severe ,rnore severe

15 20

HRC HRC MCV MCV MCV MCV

$6) The tests were performed by the Huntingdon Research Centre (BRC), England, and by the Medical College of Virginia (MCV), USA, whose cooperation we gratefully aknowledge. Considering pharmacological lack

profile

of addiction

has been allow

the

the

cessarily

liability

central

on the

other,

why and how does

splitting

of pharmacological

evidence analgesic

arising

from

activity

the

on one side,

the

question

we asked

ourselves

the

viminol

molecular

structure

properties

usually

we

consider

ne-

interdependent.

evaluation

has been

of the

oms (they

there

obtained

individual

in many natural

no1 molecule

anolic

experimental

of viminol,

following:

The answer

found

contradictory

this

is

the

substituted

connecting aminic

butyl

groups.

group

can possess,

group

Considering as it

the

isolation

stereoisoners

and synthetic

are asterisk

chain

after

central

recurrence

marked the

1):

substituted

that

other, the

the

the

than

the

asymmetric

in

present

has been the

in

in the

atom of

vimi-

carbon the

on one side

recur

carbon

2, the

also

is

group

others

As it

one asyrmnetric

first

pyrryl

shown in Fig.

viminol.

analgesic,

of more

in Fig.

on the

is

of

and the pharmacological

ateth-

and two

the

R or S configuration,

the

secondary

sec.butyl the

114

Pharmacological

following the

three

viminol

(Fig.

configurated

molecule:

the

couples

Research of

R,R , or the

Communications,

stereoisomers

Vol. 8, PJo. 2, 1976

may be presented

S,S or further

still

the

by

R,S(S,R)

3).

CH3 \ N / C2H5

S-configuration

R-configuration Figure

Figure As the isomers

2 - Absolute

3 - Absolute

ethanolic may exist,

and R,R,S

j S,S,R

chain

also

presenting and S,S,S

configuration

configuration contains the

of N-sec.butyl

of viminol an asymmetric

following

; and at last

R,S,S

stereoisomers. carbon

absolute

groups.

atom,

configuration:

and R,S,R

(Chiarino

six

stereoR,R,R et al.,

Pharmacological

in press).

Research

It

Communications,

seemed reasonable

ical

activities

sult

of mutual interaction

isomers,

of viminol

as determined

well as by their The results ferent

to us to assume, then,

between the

by their

that

differently

relative

the pharmacolog as the re-

configurated

concentration

stereo-

in the

mixture

as

potency for a given effect.

of the pharmacological

investigations

performed

into

the dif

can be summarized as follows.

The R,R configurated and repeated

physical

115

racemate we found have to be regarded

relative

stereoisomers

single

Vol. 8, No. 2, 1976

stereoisomers

administration:

exhibit

agonistic

analgesia

activities

and catalepsy,

both

tolerance

on and

dependence.

The S,S configuration

produces

of the R,R stereoisomers,

effects

which are antagonistic

be they acute (analgesia),

to those

or chronic

(physical

dependence). The S,R or Meso compounds have the property pendence producing

capacity

These experimental some general

structural

features

not present

evident

veral

important

not a rigid may lie tic

appear to be of interest

considerations

and narcotic similarity

ves such as morphinans,

but a flexible

activity. either

structure,

is present

instead

considered

an isosteric

synaptic

its

gical

so that

derivative

activity

may proceed from a possible

N-alkyl properties

of the

two

radicals presented

As to how, therefore,

sec.butyl

amines; radicals

is responsible by the viminol

molecule

is

amine alipha-

nitrogen;

molecular

se

amine group

b) a tertiary

of phenylethanolamine

molecule does

On the contrary,

the substituted

ring;

between

wellknown derivati

a) the viminol

d) the viminol

events promoted by biogenic

configuration

the viminol

of the basic heterocyclic

carbon atom is present;

that

out:

because

existing

morphine or its

can be pointed

quaternary

gestion

relation

In fact

to

in the same plane as the aromatic

nitrogen

ferent

about the

particularly

benzomorphans or phenylmorphans.

differences

de-

of the R,R stereoisomers.

results

they allow

of opposing the physical

c)

structure allowing

interference

e) the different

no may be sug-

the

with the absolute

and not the presence of dif-

for the quite

different

pharmacolg

stereoisomers.

the R,R stereoisomer

of viminol

may interact

with

116

Pharmacological

the

neuronal

receptor

macologic It

effects,

appears

a precise Casy Perhaps

it

allow

to the

a proton

the

functional

However,

for

macological

effects,

ically

aiming

the

at

Firstly

a better

these

cending ic like at a-l.,

interneurons

tract

to

the

morphine, spinal 1975)

inhibitory

the

level

the

(Kitahata

and/or control

course

that

lamina

findings

nucleus

been done

strictly

in the

reladonor

or

case of vimL

sites

involves

a very

dif

stex

some experiments

more

specif-

correlation

biological

between

evidence

about

the As

activity.

afferences

through

thalamus.

vi-

it

the

al.,

a reinforcement and Takagi,

in the

after

well-

the

as-

analgesics,

a direct 1975;

stem (Satoh

is

spinothalam-

The narcotic

et

influence

for

activation:

Le Bars

the

activity.

responsible

through

high

of phar-

at least,

of

1974;

effect

have

is known,

types

V interneurons

brain

mo-

specific

of the

peripheral

the

viminol

a proton

in producing

in part

from

very

and

molecule.

the

revealed

V interneurons

lamina

that

by Beckett

as it

membrane

some experimental

et al.,

an indirect

pha;

bonds.

and the

posteroventral depress

1975),

for

not either

to undertook

are, of

Bella,

the viminol

with

neuronal

understanding

on the

transmission

be of

structure

configuration

of R,R stereoisomers known,

provided

experimental

to obtain

the

(1965):

compounds,

and different

we decided

we tried

suitable

by Portoghese

to the

viminol

stereochemical

model

may also

as our previous

eoselectivity

a more

but

binding groups

Vol. 8, No. 2, 1976

initiating

out

for

that

It

as worked

be hypothesized

of different

group.

for

shown (Della

model

one proposed

stereospecific

ferent

cannot

(structure,

acceptor

no1 the

a receptor

fitting

morphine

required

as previously

to

the

complex

Communications,

an open question.

evident,

may be suggested is

the

really

morphine,

binding

minol

is

quite

for

it

could

ted

it

accommodation

(1954)

lecule

to form

Research

effect

Della

Bella

et

of descending 1971)

have

been

postulated. Our experiments cal

level:

el using experiment determine

the glass the the

extracellular

unitary

microelectrodes

filled

electrophoretic

injection

microelectrode

tip

cat,

recordings with

position.

were

3 Mol KCl. of pontamine The results

spinal

section

made at the At the blue

at

cervi-

lumbar

end of

leveach

was performed

obtained

are

shown

to

Pharmacological from

Fig.

taneous

4:

the

afferent

venous the

Research

Communications,

responses fibers

evoked appear

administration:

by peripheral

practically

naloxone

is

117

Vol. 8, No. 2, 1976 stimulation

abolished

able

of the

after

to reverse

small

viminol

quickly

cu-

R 2 intra-

and completely

inhibition.

EF (pinch)

240 i 220. 200. 180. 160-

-

140. P h 5 r

10 5ec.

120. 100.

0’

4

control

1 mg/kg

Figure

4 - Lamina ment.

The direct appears

i.v.

V interneuron

influence

of the

confirmed

that

only

activity

different the

--1 min. after

4 I NALOXONE 0.1 mg/kg

15 min. after

after

viminol

stereoisomers

R

is

R,R configuration

is

ix.

2

and naloxone

treat-

shown in Table provided

with

3: it

agonistic

effects. It

is

interesting

mer is vo - have

more

than

out

the

R1 is

in Fig.

figurated is

active

shown that

illustrated

It

to point

that

also

at the

R1 enantiomer:

at least

5 shows the

20-30

spinal

analgesic times

antagonistic

less effect

level assays

the

R

2 performed

active.

The

produced

by the

enantioin vi-

experiment S,S con-

S2 stereoisomer. evident

in reversing

that the

the

S2 intravenous

depressant

effect

administration by the

R

2

isomer.

is

rapidly

Considering

effective that

this

118

Pharmacological

Research

Table 3 - Morphine and viminol stereoisomers activation of lamina V inter-neurons.

3C Morphine R

-w Viminol

4

SC Vznol

R 1 S 1 S2

-',L::Viminol

Meso

on nociceptive

depression strong depression

28

2

Vol. 8, No. 2, 1976

INFLUENCE

11

*:- Viminol

%+ Viminol

influence

No. OF REGISTERED INTERNEURONS

DOSE mg/kg i.v.

COMPOURDS

Communications,

weak depression

4

no

effect

3

no

effect

6

no

effect

i as hydrochloride X- as p-hydroxybenzoate

EF (pinch)

160. 140. Y f 0 Y ,P

I;... maec.

120. 100. 60. 60. 40. 20. O-

,

control

Figure

.

4

I ’ VIMINOL 1 w/kg

5 - Lamina V interneuron ment.

c

.

Rp

T VIMINOL

i.v.

2 mglkg

15 min.

activity

after

after

,

viminol

,

.

5 min. after

S2

i.v.

stereoisomers

treat

Pharmacological

Research

interaction,

Communications,

as in the case of morphine and naloxone,

as consequent to the displacement stereoisomer, following

we then studied

the procedure

results

Vol. 8, No. 2, 1976

obtained

of R2 from the specific

their

described

binding

of viminol

VIMINOL ISOMERS

-:)

As it phine,

to the synaptosomal

The preliminary

and

AL

y.

DRUGS"

(ti)

40

MORPHINE

70

METHADONE

30

> 1000

PENTAZOCINE

50

' 2500

PROPOXYPBENE

1000

7

' 1000

Pert and Snyder (1973)

in the order of magnitude

logical

S2

fractions

stereoisomers

appears the RDso values of R,R stereoisomersare

R2 values

by

in the Table 4.

Table 4 - Synaptosomal binding morphine-like drugs.

L

receptors

by Pert and Snyder (1973).

by us are reported

R1 R 2 S 1 S 2 R,S (Meso)

could be interpreted

are not, potency.

of pentazocine

the R aild 1 in good agreement with their pharmaco-

on the contrary, As we said before,

spect to R2. But the unexpected the S2 stereoisomer,

10 times those of may

and methadone:

Rl is 20-30 times less active

result

is the very low affinity

which we found able to reverse

in

re-

shown by

the depressant

effect

of R on the spinal interneurons. Its affinity appears even lower 2 that of Sl and Meso compoundswhichwe found completely ineffective

than in &

vivo experiments. Now, if

we accept that

is consequent

on its

the influence affinity

on the lamina V interneurons

to a specific

receptor,

by R2

then the suppres

sion of such influence

the

S2 affinity

the

experimental results

by S could be possible only in the case that 2 to the same specific receptor was higher. On the contrary, evidence proves that R2 affinity

from its

is much higher.

ability

to

displace

to the

binding

site,

as

naloxone from synaptosomal fraction,

it

120

Pharmacological

It is reasonable nation tion

of this

finding

is the occurrence and antagonist

interaction

To obtain

further

testinal

The influence

structures

and its

ously illustrated Kosterlitz,

displayed

evaluation

results

experimental

it

is quite

the R,R configurated

but also

of

and the mecha-

between the viminol

of their

agonists

Kosterlitz

we obtained

conditions

evident

effects

stimc

and antagonists

features

ste

on the in-

electrically

on these

have been

and Lees, 1964;

previ-

Waterfield

are summarized in the

that

usually

values

and

activity

activity

analgesic

hot plate test (mice)a

tail flick test (ratsIb

stereoisomers.

acetic acid stretthing test (mice)c

R1

z 20

17.5 (11.7-26.2)

(14.624.8)

R 2

1.15 (0.8-1.5)

0.71 (0.49-1.03)

(1.4Z)

5

> 40

’ 40

‘> 40

S

> 40

> 40

> 40

’ 40

> 40

P- 40

2 R,S(Meso)

Eddy et al. (1950) D'Amour and Smith (1941) Koster et al. (1959)

properby

being the most active.

ED5o (mg/kg s.c.) VIMINOL ISOMERS

dose 50 in

is possessed only

the R2 enantiomer

of viminol

following

of the effective

adopted to test

the analgesic

stereoisomers,

Table 5 - Analgesic

a) b) c)

interac-

and types of attack.

nervous terminals

The Table 5 shows the comparative

different

expla-

1975).

The experimental tables.

existing

by narcotic

1957;

site,

sites

dependence on stereochemical (Paton,

a satisfactory

about the nature

and interactions

smooth muscle and cholinergic

lated.

ties:

evidences

the in vitro

Vol. 8, No. 2, 1976

not only of a molecular

from different

experimental

we undertook

that

at the same binding

resulting

nism both of the activity reoisomers

Communications,

to suppose, in our opinion,

between agonist

a functional

Research

Pharmacological

Research

Communications,

12 ‘1

Vol. 8, No. 2, 1976

Both the S,S and the Meso compounds have to be considered fective.

When we tried

acetylcholine

release

compounds tested rated

to correlate

possess an inhibitory

activity,

found between the resting by electrical

and influence stereoisomers.

has been provoked

IN VITRO ACh RELE E % (GUINEA-PIG z3uM) ID5o (mol. cont.) -6 10 8 x IO-7

I‘ 20

1 x

1.15

s1

> 40

s2

> 40 ’ 40

R,S(Meso) Eddy et al.

(1950);

both on the acetylcholine stereoisomers values,

tor responses:

appear to be active

finding

is,

dependence between reduction of the electrically

As regards the influence by viminol unexpectedly

stereoisomers,

existing

between the inhibitory

release and the motor responses.

the S,S stereoisomers this

-8 7 x 10 -8 5 x 10 8 x IO-7

b) Paton (1957)

The Table 7 shows the correlation

reoisomers.

only with antagonistic

of acetylcholine

2

erties

the

on the acetylcholine

IN VIVO ANALGESICACTIVITY (HOT PLATE TEST IN MICE)a JD5o bdkg s.c.)

R 1 R

tration

all

stimulation.

VIMINOL ISOMERS

figurated

on the

the S,S configu-

compounds. No difference

release and the release

Table 6 - Analgesic activity release by viminol

a)

not only that

but that

as we have demonstrated

appear to be the most active

inef-

to the influence

(Table 6), we found unexpectedly

stereoisomers , provided

properties,

these properties

practically

potency

While the R,R COE

about at the same molar concen-

are clearly

in our opinion,

of acetylcholine

less effective against

on the mo-

a necessary inter-

release and inhibitory

prop-

provoked motor responses. of naloxone on the intestinal the results

obtained

naloxone is able to antagonize

motor inhibition

(Table 8) demonstrate

that

both the R,R and the Meso ste-

122

Pharmacological

Research

Communications,

Vol. 8, No. 2, 1976

Table 7 - Influence of viminol stereoisomers on the acetylcholine release and the motor responses of guinea-pig ileum to electrical stimulation. .VIMINOL ISOMERS

ACh RELEASElD MOL. CONC. 50

R 1 R 2

1 x 10 8 x 10-7

MOTORRESPONSES ID MOL. CONC. 50

-6

-6

1.3 x 10 2.4 x 10-7

-8 7 x 10 -8 5 x 10 8 x lo -7

3 s2 R,S(Meso)

-6

1.7 x 10 1.8 x 10-6 -6

1.4 x 10

Table 8 - Influence of naloxone and CaC12 on the inhibitory activity of viminol stereoisomers on guinea-pig ileum responses to electrical stimulation.

VIMINOL ISOMERS

NALOXONE (75 Ml

R 1 R2 S 1 s2 R,S(Meso)

Naloxone does not modify, S,S stereoisomers. R,R stereoisomers

reversal

reversal

reversal

unchanged

reversal

unchanged

reversal

reversal

reversal

on the contrary,

No antagonistic

from the works of Nutt

effect

the inhibition

influence

have been detected.

calcium on the inhibitory

of the S,S

Table 8 also

of viminol

is antagonized,

define

moment how important

not competitively, this

correlation

produced by

the

compounds on

the

shows the influence

stereoisomers.

(1968) and Kakunaga et al.

phine activity at this

reversal

of

It is wellknown

(1966) that

also the mor

by calcium:

it

is to explain

is hard to the mecha

Pharmacological

Research

Communications,

Vol. 8, No. 2, 1976

nism by which morphine and viminol

reduce the electrically

provoked intest&

nal motility. We think

however that

could be a suggestive complex formation

a chelation

hypothesis.

only requires

the amine group on one side, steric

orientation

Figure

As it

difference

6, if

stereoisomers the

calcium

between the cation

group on the other,

and

than the

groups has only a secondary role.

viminol-calcium

complex formation.

and acetylcholine

release are strictly

becomes obvious why we did not find

between the differently

New experiments

bonds

and the hydroxyl

As the calcium ions concentration then it

is shown in Fig.

coordination

of the sec.butyl

6 - Hypothetical

terdependent,

of calcium by the viminol

configurated

are in progress

to clarify

viminol this

ig

any substantial

stereoisomers.

problem.

CONCLUSIONS The conclusions logical

activities

of our studies

on viminol

are the following:

molecular

configurations

and bio-

124

1)

Pharmacological

First

of all,

it

and

synthetic

has been proved that, morphine-like

pyrryl-ethanolamine, tagonistic 2)

Research

Communications,

in addition

Vol. 8, No. 2, 1976

to the known natural

compounds, a new molecular

is able to produce both narcotic

structure, agonistic

the and an-

effects.

Like morphine,

at spinal

level

the R,R configurated

mers depress the lamina V interneurons ciceptive

stimulation.

This effect

viminol

stereoiso-

activation

by peripheral

is specifically

antagonized

noby

the

S,S stereoisomers. 3)

The antagonism

by the S,S stereoisomers

of competitive

displacement

reoisomers;

unlike

the R,R

therefore

in our opinion,

be regarded, properties,

(1972),

All viminol release

agonistic

duction

mine the inhibition fact, 6)

there

is no

A non stereospecific reoisomers influence Finally,

be supported,

of electrically correlation

interaction

consideration: structures

as postulated

by

of yet

un-

passive drugs,

only

reduce acetylcholine completely

of

inhibition.

stereoisomers,

that

factor

intestinal

a re

to deter-

motility:

between calcium ions and viminol explanation

the interest

provided

so as to make available

devoid

in

between the two effects.

release.

tools

properties

for the modulation

stimulated

on acetylcholine

also new pharmacological

own

is the only important

as a possible

develop new molecular

with their

for the viminol

is postulated

a general

as provided

produce the strongest

release

clear

not should

S,S stereoisomers,

at least

of acetylcholine

do

free.

activities,

There is no evidence,

of the R,R ste-

antagonists

(R,R , S,S and Meso)

ileum.

in term

The narcotic

and not as indirect,

sites

configurations

by guinea-pig

narcotic

responsible

functions,

able to make the binding

sites.

the "abstinoid"

directly

known physiological

site

compounds the S,S stereoisomers

binding

Villarreal

5)

from the same binding

bind to the synaptosomal

pharmacological

4)

can not be interpreted

of their

to identify,

with narcotic

we need to clarify

inhibitory

study and

properties

not only new therapeutic

ste-

has to

agents,

the structure-activity

but

Pharmacological

Research

relationship,

the mechanism and site

quently,

their

precise

Communications,

125

Vol. 8, No. 2, 1976

of action

of narcotics

and, conse-

value.

REFERENCES BABBINI M. and DAVIS W.M. (1967)

- The Pharmacologist

BABBINI M., GAIARDI M. and BARTOLETTIM. (1973)

9, 219.

- Europ. J. Pharmacol. 2&

137.

BECKETTA.H. and CASYA.F.

(1954)

- J. Pharm. Pharmac. 6, 986.

BUZZELLI G., GRAZZINI M. and MONAFOV. (1970)

- Cur-r. Ther. Res. 12, 561.

CHIARINO D., DELLA BELLA D., JOMMI G. and VENEZIANI C. - J. Med. Chem., in press. D'AMOURF.E. and SMITH D.L.

(1941) - J. Pharmacol.

72, 74.

DELLA BELLA D., FERRARI V., FRIGENI V. and LUALDI P. (1973) Biology 241, 282.

- Nature New

DELLA BELLA D. and LUALDI P. (1974) - Proceedings of the "2nd Congress of the Hungarian Pharmacological Society", Budapest, October 2-5, 1974, in press. DELLABELLAD.,

BENELLI G. and BESSONJ.M. (1975) - Life

DELLA BELLA D. (1975) - Neuropharmacol.

l&

Sci. 17, 73.

in press.

C. and LIEBERMANJ.E. EDDYN.B., FUHRMEISTERTOUCHBERRY macol. 98, 121.

(1950)

- J. Phar-

FRIGERIO G. (1974)

- Minerva Med. -65 (suppl. 12), 687. KAKUNAGA T., KANETOH. and HAN0 K. (1966) - J. Pharmac. Exp. Ther. 153, 134. KITAHATAL.M., sthesiology

KOSAKAY., TAUB A., BONMOSK. and HOFFERTM. (1974) - Ane4l, 39.

KOSTERR., ANDERSON M. and DE BEERE.J. KOSTERLITZH.W. and LEES G.M. (1964)

(1959) - Fed. Proc. l8,

- Pharmacol. Rev. l6,

412.

301.

LE BARSD., ME&TREY D ., CONSEILLERC. and BESSONJ.M. (1975) - Brain Research 98, 261. MARTINETTI L., cd.

lo,

LODOLAE., MONAFOV. and FERRARI8.

(1970) - J. Clin.

Pharma-

390.

MARTMETTI L. and MONAFOV. (1971) NUTT J.G. (1968) - Fed. Proc. 3, PATONW.D.M. (1957) - Brit.

- Int.

J. Clin.

Pharmacol. 4, 298.

753.

J. Pharmacol. 12, 119.

PERT C.B. and SNYDERS.H. (1973) - Proc. Nat. Acad. Sci.

(USA) z,

2243.

126

Pharmacological

Research

Communications,

Vol. 8, No. 2, 1976

PORTOGHESE P.S. (1965) - J. Med. Chem. 8, 609. SAELENSJ.K., GRANATF.R. and SAWYER W.K. (1971) - In: ItCommittee on Problems of Drug Dependence", 32nd Annual Meeting, Toronto, February 16-17, 1971, Vol. II, p. 1310. SATOHM. and TAKAGI H. (1971) - Europ. J. Pharmacol. 14, 60. TEOTINOU.M. and DELLA BELLA D. (1967) - Belgian

Patent 698,568.

TEOTINOU.M., DELLA BELLA D., VENEZIANI C. and CHIARINO D. (1972) - Belgian Patent 790,747. VILLARREAL J.E. (1972) - In: "Agonist and Antagonist Analgesic Drugs", Kosterlitz H.W., Collier H.Q.J. Editors, Macmillan, London, p. 73. WATERFIELDA.A. and KOSTERLITZH.W. (1975) - Life

Actions of Narcotic and Villarreal J.E.

Sci. 16, 1787.