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1 Pharmacological Activities of 14-Acylaminomorphinones, 14-Alkylaminomorphinones, the Equivalent Codeinones and Their 17-Cyclopropylmethyl Analogues

1 Pharmacological Activities of 14-Acylaminomorphinones, 14-Alkylaminomorphinones, the Equivalent Codeinones and Their 17-Cyclopropylmethyl Analogues

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14-Amino-4,5-Epoxymorphinan Derivatives and Their Pharmacological Actions



101



Table 1 In vitro and in vivo agonist activity of compounds of structures 36 and 37 (Fig. 2)

In vitro potency

In vivo potency

R00

times normorphinea

times morphineb

36a

Me

0.1

0.17

n-Pr

2.1

2.8

n-Bu

3.7

3.8

n-Pent

77

27

n-Hex

168

31

n-Hept

36

8.9

36c



37a



37c



Me

n-Pr

n-Bu

n-Pent

n-Hex

n-Hept

Ph

CH2Ph

(CH2)2Ph

(CH2)3Ph

(CH2)4Ph



0.4

32

191

4000

628

394

38

272

744

490

32



0.44

12

56

117

82

61

18

148

222

7.0

11



Me

Et

n-Pr

n-Bu

n-Pent

n-Hex

n-Hept



0.2

0.15

0.25

0.9

8.1

30

46



0.67

0.73

2.4

2.0

6.6

73

9.4



n-Pr

20

n-Bu

39

n-Pent

220

n-Hex

1,000

n-Hept

538

n-Oct

289

CH2Ph

32

(CH2)2Ph

3370

(CH2)3Ph

1,500

(CH2)4Ph

508

(CH2)5Ph

329

a

Determined in the mouse vas deferens

b

Determined in rat tail pressure test



65

11

297

980

408

153

34

2512

ND

ND

ND



antagonists. The heptylamino- derivative retained potent antagonism in vitro but

also had mouse vas deferens agonist activity of greater potency than normorphine.

It was also active in the rat tail pressure test of analgesic activity (Table 2).

From the initial evaluation of the large number of 14-acylamino- and 14-alkylaminocodeinones and morphinones synthesised in the Reckitt and Colman programme,

it became clear that the C14 side chains of particular interest were those with an

aryl group joined to C14 by an alkyl group of two to four carbon atoms with three

carbon chain compounds having special qualities. Lewis et al. [14] revealed



102



J.W. Lewis and S.M. Husbands



Table 2 In vitro and in vivo activity of compounds of structure 36 and 37 (Fig. 2)

R00

Agonist in vitro

Antagonist

Agonist in vivo

Antagonist

potency times

in vitro potency

potency times

in vivo potency

normorphinea

times naloxoneb

morphinec

times naloxoned

H

36b

0.1

0.1

ND

<0.01

Me

0.3

ND

ND

<0.01

Et

<0.1

0.1

ND

ND

n-Pr

<0.1

1.0

1.0

ND

n-Bu

<0.1

4.9

49

ND

n-Pent

<0.1

22

11

ND

n-Hex

<0.1

33

13

ND

n-Hept 23

<0.1

0.55

ND

36d

H

6.0

ND

ND

0.03

Me

1.0

ND

ND

ND

Et

3.0

<0.1

ND

0.07

n-Pr

2.0

0.1

10

<0.01

n-Bu

1.0

3.7

30

ND

n-Pent

2.0

23

136

<0.1

n-Hex

0.5

32

100

<0.05

37d

H

3.0

<0.1

ND

0.28

Me

1.0

<0.1

ND

0.28

n-Bu

1.0

ND

ND

0.09

n-Pent

0.5

<0.1

ND

0.12

n-Hex

0.7

<0.1

ND

0.02

n-Hept 3.0

0.5

0.5

0.05

n-Oct

1.3

ND

0.5

<0.05

CH2Ph <0.01e

1.0

0.33

ND

ND not determined

a

Determined in mouse vas deferens

b

Determined in mouse vas deferens vs normorphine

c

Determined in rat tail pressure assay

d

Determined in rat tail withdrawal vs morphine

e

53 times normorphine in guinea pig ileum



NR' H

N



NR'



R"



N



NHR"



NH 2



O

O

RO



O



36a: R = Me, R' = Me

36b: R = Me, R' = CPM

36c: R = H, R' = Me

36d: R = H, R' = CPM



O



RO



O

37a: R = Me, R' = Me

37b: R = Me, R' = CPM

37c: R = H, R' = Me

37d: R = H, R' = CPM



O

HO



38



O



Fig. 2 14-Acyl- and 14-alkylaminomorphinones and codeinones



structure–activity relationships relating to substitution in the aromatic ring of the

cinnamoylamino group, the effect of hydrogenation of cinnamoylamino to dihydrocinnamoylamino and morphinone to 7,8-dihydromorphinone as well as the



14-Amino-4,5-Epoxymorphinan Derivatives and Their Pharmacological Actions



4'



NR H

N



N



3'

2' R"



R"

O



O

39



H

N

O



O

R'O



103



O



R = Me or CPM

R' = H or Me

R" = 2'- and 4'-Me, F, Cl, Br



R'O



40



O



(a) R' = Me, R" = 4'-Cl, MC-CAM

(b) R' = Me, R" = 4'-Br

(c) R' = Me, R" = 4'-Me, MM-CAM

(d) R' = H, R" = 4'-Cl, C-CAM

(e) R' = H, R" = 4'-Br

( f ) R' = H, R" = 4'-Me, M-CAM



Fig. 3 14-Cinnamoylamino analogues



more usual relationships between codeinones and morphinones and 17-methyl to

17-cyclopropylmethyl groups (39) (Fig. 3). There was a clear effect of orientation

of chloro and methyl groups, but not fluoro, in the cinnamoyl group; 40 -substitution

substantially reduced MOR agonist efficacy whereas 20 - and 30 -substitution appeared

to have relatively little effect when compared to the unsubstituted cinnamoylamino

group. Thus the cinnamoylaminomorphinone 39 (R = Me, R0 = R00 = H) and its

analogues substituted in the aromatic ring with 20 -chloro, 20 -methyl and 40 -fluoro

groups had potencies as agonists in the mouse vas deferens assay of between 353 and

585 times that of normorphine. In the rat tail pressure in vivo assay they had ED50

values between 0.003 mg/kg and 0.014 mg/kg compared to morphine’s ED50

of 0.66 mg/kg. The effect of hydrogenation of the 7,8-double bond was to reduce

opioid receptor efficacy, though not dramatically; hydrogenation of the cinnamoylamino side-chain resulted in a more substantial increase in MOR efficacy [14].



3.2



Pharmacological Actions of 14-Cinnamoylamino17-Cyclopropylmethyl-7,8-Dihydronormorphinones

and Equivalent Codeinones



Attention was drawn to the 40 -substituted 14-cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronorcodeinones and equivalent morphinones (40) (Fig. 3). Of

particular interest to Reckitt and Colman’s target of buprenorphine-like opioid

activity were the dihydrocodeinones (40a–c) from which the 40 -chloro derivative,

called methoclocinnamox (40a, MC-CAM), was selected for detailed study. The

Reckitt and Colman group had shown the three 40 -substituted dihydrocodeinones

(40a–c) to be predominantly MOR partial agonists of long duration in vivo [14].

Importantly, MC-CAM showed bell-shaped dose–response curves in both tail

withdrawal and tail pressure antinociceptive assays. In this respect and in the

inability of naltrexone to reverse its antinociceptive effect, as well as its longlived morphine antagonism, its similarity to buprenorphine was demonstrated.



104



J.W. Lewis and S.M. Husbands



The 40 -substituted dihydrocodeinones and morphinones (40) were the subject of

a detailed study by the Drug Evaluation Committee of the National Institute on

Drug Abuse [22]. This study confirmed, in a battery of mouse antinociceptive

assays and in morphine-dependent rhesus monkeys, the long-acting MOR partial

agonist activity of MC-CAM and its analogous 40 -bromo- and 40 -methylcinnamoylaminodihydrocodeinones. The dihydromorphinone (40d, clocinnamox; C-CAM)

related to MC-CAM and the related 40 -bromo- (40e) and 40 -methylcinnamoylamino- (40f, M-CAM) analogues were shown to have little or no antinociceptive

activity in mice but to have extremely long duration of morphine antagonism in the

tail flick (TF) assay [22].

In withdrawn morphine-dependent rhesus monkeys, the morphinones exacerbated withdrawal at very low doses. Withdrawal effects persisted even after morphine administration (3 mg/kg, 6 hourly) was resumed [23]. Self-administration and

drug discrimination studies in rhesus monkeys were also included in this report.

In the drug discrimination assay the codeinones all generalised to codeine. The

40 -bromo- and 40 -methylcinnamoylaminodihydrocodeinones (40b, 40c) were also

self-administered but at rates that were below those of codeine [22]. These results

confirmed the MOR partial agonist character of the codeinones.

Preliminary metabolism studies in rats and cynomolgus monkeys showed that

MC-CAM was substantially O-demethylated to C-CAM [14]. Thus the delayed

long-term morphine antagonism displayed by MC-CAM could have been caused by

its transformation to C-CAM. That this was probably not the case was later shown

by i.c.v. administration of MC-CAM which resulted only in MOR antagonist

activity [24].

Investigations of the detailed pharmacology of C-CAM were initiated by

Woods and collaborators. Comer et al. [25] used the TW test to assess the

antinociceptive effects of morphine and fentanyl in the presence of C-CAM.

Low doses of C-CAM (e.g. 3.2 mg/kg) produced rightward shifts in the dose–

response curves of both morphine and fentanyl whereas high doses (>3.2 mg/kg)

substantially depressed the maximum effect of morphine with the highest dose

(32 mg/kg) also producing the suggestion of suppression of the effect of fentanyl.

This is consistent with the designation of fentanyl as a more efficacious MOR

agonist than morphine and suggested an irreversible MOR antagonist effect

of C-CAM. The highest dose of C-CAM (32 mg/kg) antagonised the antinociceptive effect of morphine for up to 8 days. The irreversible nature of C-CAM’s

MOR antagonism was confirmed in vivo and in binding experiments by

Burke et al. [26]. However, when mouse brain membranes were incubated with

[3H]C-CAM followed by precipitation of the protein, no specific radiolabelling of

receptor protein was seen, suggesting C-CAM did not bind covalently to MOR.

Following the initial evidence of C-CAM’s ability to rank efficacy of MOR

agonists [25], it was reported that C-CAM could be utilised to give efficacy

and apparent affinity estimates for MOR agonists in mice [27], rhesus monkeys

[28] and squirrel monkeys [29]. Relative efficacies of MOR agonists in drug

discrimination assays using C-CAM have also been reported in pigeons [30] and

rats [31].



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1 Pharmacological Activities of 14-Acylaminomorphinones, 14-Alkylaminomorphinones, the Equivalent Codeinones and Their 17-Cyclopropylmethyl Analogues

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