Structure-Behavioral Activity Relationships of Peptides Derived from

7 Structure-Behavioral Activity Relationships of Peptides Derived from ACTH Some Stereochemical Considerations

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J. W. V A N N I S P E N and H . M . G R E V E N Organon Scientific Development Group, 5340 B H Oss, The Netherlands

The influence of chain length and side-chain modifica tions of ACTH-derived peptides on active avoidance behaviour in rats will be discussed. H - M e t ( O ) - G l u - H i s - P h e - D - L y s - P h e - O H (Org 2766) emerged from these studies as an orally active peptide with an increased potency and selectivity of action. Physico-chemical data (from the literature) on the reference peptide A C T H -(4-10) did not point to a preferred conformation in solution, whereas in the crystalline state an antiparallel β-pleated sheet structure was found. At the receptor site we suggested an α-helical conformation in which the Phe and Met residues are close together. Additional support for this suggestion came from the behavioural activity of [des-Tyr , Met ]enkephalin and of cyclo- ( - P h e - M e t - є A h x - ) , єAhx merely serving as a spacer. 2

1

5

T h e r e l a t i o n s h i p b e t w e e n t h e s t r u c t u r e of a s e r i e s of p e p t i d e s d e r i v e d f r o m the a d r e n o c o r t i c o t r o p i c h o r m o n e A C T H , behavioural activity

a n d the

in an a c t i v e a v o i d a n c e behaviour t e s t ,

s t u d i e d over the past 10-20

has been

y e a r s . The results obtained were quite

different f r o m those in w h i c h e n d o c r i n e a c t i v i t y r e l a t i o n s h i p s were s t u d i e d . F r o m t h e o u t c o m e of a q u a n t i t a t i v e

study on the

structure-

- b e h a v i o u r a l a c t i v i t y of t h e A C T H - r e l a t e d p e p t i d e s , s u g g e s t i o n s about the s p a t i a l

i n t e r a c t i o n s at the r e c e p t o r s i t e w e r e m a d e .

This

r e c e p t o r - b o u n d c o n f o r m a t i o n differed f r o m t h o s e s u g g e s t e d by s o l u t i o n e x p e r i m e n t s or f o u n d i n c r y s t a l

structures.

In t h i s p a p e r w e w i l l i l l u s t r a t e t h e l i n e of r e s e a r c h t h a t w a s f o l l o w e d in the s t r u c t u r e - b e h a v i o u r a l

a c t i v i t y work a n d that r e s u l t e d

0097-6156/ 84/ 0251 -0153506.00/ 0 © 1984 American Chemical Society

Vida and Gordon; Conformationally Directed Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

154

CONFORMATIONALLY DIRECTED DRUG DESIGN

i n a m o d i f i e d h e x a p e p t i d e w i t h a n i n c r e a s e d s e l e c t i v i t y of a c t i o n ; d i s s o c i a t i o n of a c t i v e a v o i d a n c e b e h a v i o u r a l a c t i v i t y f r o m o t h e r a c t i v i t i e s w i l l be m e n t i o n e d b r i e f l y . W e w i l l a l s o d e s c r i b e the a r g u m e n t s t h a t h a v e l e d t o t h e p r o p o s a l of a n a - h e l i c a l for t h i s h e x a p e p t i d e at t h e r e c e p t o r

conformation

site.

S t r a t e g y a n d r e s u l t s of t h e s t r u c t u r e - b e h a v i o u r a l a c t i v i t y

ACTH,

studies

a s t r a i g h t - c h a i n p e p t i d e of 3 9 a m i n o a c i d r e s i d u e s ( F i g u r e

1),

h a s b e e n t h e s u b j e c t o f e x t e n s i v e s t u d i e s b y m a n y g r o u p s . In a d d i -


t i o n t o s t i m u l a t i o n of t h e a d r e n a l c o r t e x i n v e r t e b r a t e a n i m a l s a n d man,

lipolytic and melanotropic effects are important,

extra-adrenal

activities

(1,

2).

a l s o affected behaviour in intact (4).

systemic,

In t h e f i f t i e s it w a s f o u n d t h a t (3)

ACTH

and hypophysectomized a n i m a l s

T h e m e l a n o c y t e - s t i m u l a t i n g h o r m o n e s a - M S H ( c o m p r i s i n g the

N-terminal

13 a m i n o a c i d r e s i d u e s of A C T H b u t w i t h b l o c k e d e n d

g r o u p s , s e e F i g u r e 1) a n d ( 3 - M S H ( c o n t a i n i n g , sequence 4-10 impairment lobe ( 5 ) .

in g e n e r a l ,

the

of A C T H ) w e r e a l s o a b l e t o c o r r e c t b e h a v i o u r a l

i n r a t s a f t e r r e m o v a l o f t h e p i t u i t a r y or o n l y i t s a n t e r i o r

S i n c e that t i m e the i n f l u e n c e of s t r u c t u r a l

modifications

of t h e s e p e p t i d e s o n b e h a v i o u r i n r a t s h a s b e e n i n v e s t i g a t e d , e s p e c i a l l y by d e W i e d a n d c o - w o r k e r s . T h e f i r s t s t e p in t h e s e s t u d i e s h a s b e e n the s e a r c h for t h e s h o r t e s t f r a g m e n t of t h e A C T H c h a i n t h a t i s e s s e n t i a l for of)

activity.

Next,

(maintenance

c h a n g e s in the peptide b a c k b o n e and m o d i f i c a -

t i o n of t h e s i d e - c h a i n s o f t h e a m i n o a c i d r e s i d u e s h a v e b e e n s t u d i e d . A s a t e s t s y s t e m t h e d e l a y of e x t i n c t i o n of a n a c t i v e a v o i d a n c e r e s p o n s e in rats a s m e a s u r e d in a p o l e - j u m p i n g test after

sub-

c u t a n e o u s a d m i n i s t r a t i o n h a s b e e n u s e d (7) ; t h i s a s s a y m e t h o d g i v e s a g r a d e d d o s e - r e s p o n s e r e l a t i o n s h i p w h i c h a l l o w s the e s t i m a t i o n of a n -(4-10)

ED50

1

and thus potency ratio s . The heptapeptide

h a s been u s e d a s the reference peptide ( 8 ) .

extensive review see ref.

I n f l u e n c e of c h a i n l e n g t h .

ACTH-

For a m o r e

9.

T h e f r a g m e n t s 1-24

a n d 1-10

were as

a c t i v e a s the w h o l e m o l e c u l e (weight b a s i s ) in d e l a y i n g e x t i n c t i o n of t h e a c t i v e a v o i d a n c e r e s p o n s e , w h e r e a s t h e C - t e r m i n a l 25-39,

18-39

(both porcine s e q u e n c e ) and 11-24

of t h a t p o t e n c y . S t e p w i s e s h o r t e n i n g f r o m t h e N - a n d , f r o m the C - t e r m i n a l

fragments

possessed

1/10th

separately,

end resulted in fragment 4 - 7 w h i c h c o n t a i n e d

a l l t h e e s s e n t i a l e l e m e n t s for a f u l l r e s p o n s e ( 1 0 ) .

ACTH-(7-10)

e x e r t e d a c o m p l e t e r e s p o n s e o n l y at a 10 t i m e s h i g h e r d o s e ;


this

7.

VAN NISPEN AND GREVEN

Peptide Structure-Behavioral

Activity

155

r e s i d u a l p o t e n c y c o u l d be i n c r e a s e d to the s a m e l e v e l a s the r e f e r e n c e p e p t i d e by e x t e n s i o n to A C T H - ( 7 - 1 6 ) - N H

(11).

2

c o n c l u d e d that r e g i o n s other than the 4 - 7 a l s o c o n t a i n

It

was

information

for p o l e - j u m p i n g a c t i v i t y but t h a t t h i s i s p r e s e n t i n a l a t e n t f o r m w h i c h n e e d s c h a i n e l o n g a t i o n in order to b e c o m e f u l l y e x p r e s s e d (11).

H-Ser

-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-


-Lys-Lys-Arg-Arg-Pro-Val-Lys-Val -Tyr-Pro

2 4

-Asn-Gly-Ala-Glu-

-Asp-Glu-Ser-Ala-Glu-Ala-Phe-Pro-Leu-Glu-Phe

Figure 1.

1

Val-NH

1 3 2

]ACTH-(1-13).

sequence is A C T H - ( 4 - 1 0 ) .

-OH

(6) . a - M S H

A m i n o a c i d s e q u e n c e of h u m a n A C T H [Ac-Ser ,

3 9

is

The underlined

S t a n d a r d a b b r e v i a t i o n s are

u s e d for a m i n o a c i d s : I U P A C - I U B C o m m i s s i o n o n B i o c h e m i c a l N o m e n c l a t u r e , E u r . J . B i o c h e m . 1975, 1-14;

1972,

27,

I n f l u e n c e of D - a m i n o a c i d s . w o r k , the A r g

8

53

201-7.

A s w a s f o u n d in a n e a r l y s t a g e of t h i s

r e s i d u e c o u l d be r e p l a c e d by L y s

3

(which is simpler

in a s y n t h e t i c a l s e n s e ) w i t h o u t l o s s of a c t i v i t y . T h e r e f o r e , the

L/D

3

r e p l a c e m e n t s h a v e b e e n c a r r i e d out o n the L y s - c o n t a i n i n g h e x a peptide 4 - 9 ,

i.e.

H - M e t - G l u - H i s - P h e - L y s - T r p - O H (which is as 4

5

potent a s the s e q u e n c e 4 - 1 0 ) . T h e a n a l o g u e s w i t h D - M e t ,

D-Glu ,

D - H i s ^ or D - T r p 9 w e r e a s a c t i v e a s or m o r e a c t i v e t h a n t h e a l l - L r e f e r e n c e p e p t i d e . I n c o r p o r a t i o n of D - A r g

3

in A C T H - ( 4 - 1 0 )

resulted

in a 3 - f o l d i n c r e a s e i n p o t e n c y w h e r e a s i n c o r p o r a t i o n of D - L y s the s e q u e n c e 4 - 9 r e s u l t e d in a 10-30 R e p l a c e m e n t of P h e

7

by D - P h e

7

however,

s h o w e d a r e v e r s a l of the e f f e c t i . e . extinction (12).

3

in

times more active compound. gave a compound which

a c c e l e r a t i o n i n s t e a d o f d e l a y of

Other A C T H a n a l o g u e s c o n t a i n i n g a D - a m i n o

acid

r e s i d u e i n p o s i t i o n 7 a l s o s h o w e d a c c e l e r a t i o n of e x t i n c t i o n ( 9 ) • C o m b i n a t i o n s of t w o D - a m i n o a c i d r e s i d u e s h a d d i f f e r e n t e f f e c t s . For i n s t a n c e , c o m b i n i n g D - G l u

5

or D - H i s ^ w i t h D - L y s

somewhat more active compounds. However, ACTH-(4-9)

3

r e s u l t e d in

4

[D-Met ,

D-Lys8]-

w a s l e s s a c t i v e than the reference p e p t i d e , m e a n i n g a 3

l o s s o f t h e p o t e n t i a t i n g c o n t r i b u t i o n of D - L y s . T h e c o m b i n a t i o n o f D-Met

4

and D - P h e

7

(in the L - L y s

3

containing 4-9 peptide)

i n a l o s s o f a c c e l e r a t i o n of e x t i n c t i o n ( t y p i c a l

for D - P h e

7

resulted modifica-


156


t i o n s ) , the new a n a l o g u e b e i n g a s a c t i v e a s A C T H - ( 4 - 1 0 ) retarding e x t i n c t i o n . 7

A l s o when c o m b i n i n g D - P h e

8

[D-Phe ,

9

D-Lys , Phe ]ACTH-(4-9)

4

Met(O)

in A C T H - ( 4 - 1 0 )

in

and D - L y s

a d e l a y of e x t i n c t i o n

o b s e r v e d w i t h a r e l a t i v e p o t e n c y of o n l y

M o d i f i c a t i o n s of s i d e - c h a i n s .

7

3

a s in

was

2.

O x i d a t i o n of t h e M e t

r e s u l t e d in a 3-10

4

r e s i d u e to

times more

potent

p e p t i d e . Further o x i d a t i o n to the c o r r e s p o n d i n g s u l f o n e i n c r e a s e d the p o t e n c y t o 10 t i m e s t h a t of t h e r e f e r e n c e p e p t i d e . F i n a l l y , 8

9

[D-Lys ,

Phe ]ACTH-(4-9)

o x i d a t i o n of M e t

4

p r o d u c t t h a t w a s 1000 t i m e s a s a c t i v e a s A C T H - ( 4 - 1 0 )


in

to the s u l f o n e g a v e a while

corresponding sulfoxide analogue was slightly more active times A C T H - ( 4 - 1 0 ) ] .

R e p l a c e m e n t of M e t

4

by p - A l a ,

the

[3000

A i b , or V a l

d i d n o t y i e l d p e p t i d e s w i t h p o t e n c i e s g r e a t e r t h a n t h a t of t h e M e t ( 0 ) ^ m o d i f i c a t i o n . Protection against an

aminopeptidase-type

2

of d e g r a d a t i o n b y r e p l a c e m e n t of M e t (Dam)

or of M e t ( 0 2 )

4

by D a m ( 0 2 ) ,

p o t e n c y b y a f a c t o r of 3 .

Similarly,

4

by

desaminomethionine

r e s u l t e d i n a n i n c r e a s e of protection against a carboxy-

p e p t i d a s e - t y p e of d e g r a d a t i o n b y i n t r o d u c i n g t r y p t a m i n e tryptophan, Tra)

or a m p h e t a m i n e

(replacement

b y a C H g g r o u p ) at t h e C - t e r m i n a l

Tra ]ACTH-(4-9)

4

r e m o v a l of M e t activity,

4

9

respectively, 4

2

D-Lys ,

2

this

new

ACTH-(4-10).

from unmodified A C T H - ( 4 - 9 )

from A C T H - ( 4 - 1 0 )

r e s i d u e in [ M e t ( 0 ) ,

8

[Dam(0 ) ,

, resulted in a 10-fold potentiation;

a n a l o g u e i s 1 0 , 0 0 0 t i m e s a s potent a s A l t h o u g h r e m o v a l of T r p

9

D-Lys , Phe ]ACTH-(4-9)

c o n s i d e r a b l e l o s s of a c t i v i t y

or

r e s u l t e d i n n o a n d s o m e l o s s of

l e a v i n g o u t t h e N - or C - t e r m i n a l 8

Phe

g a v e a 3 - f o l d i n c r e a s e in p o t e n c y .

A c o m b i n a t i o n of b o t h t y p e s of m o d i f i c a t i o n , 9

(descarboxy-

of t h e C O O H of

amino acid

r e s u l t e d in a

( b y a f a c t o r of 1000 a n d 3 0 - 1 0 0 ,

r e s p e c t i v e l y ) . S o for p o t e n t i a t i o n t h e p r e s e n c e of t h e s i d e - c h a i n s of 4

Met(0 ) , 2

D-Lys

8

and P h e

9

s e e m s t o b e of p r i m e

importance.

A s m e n t i o n e d a b o v e , e l o n g a t i o n of t h e s e q u e n c e 7 - 1 0 -(7-16)-NH 4-10.

2

to

i n c r e a s e d t h e p o t e n c y t o t h a t of t h e r e f e r e n c e 8

R e p l a c e m e n t of A r g - T r p

9

8

9

by D - L y s - P h e

ACTHpeptide

resulted in a

100-

- f o l d i n c r e a s e i n p o t e n c y . C - or N - t e r m i n a l s h o r t e n i n g of t h i s

7-16

a n a l o g u e by o n l y one a m i n o a c i d r e s i d u e r e s u l t e d , a g a i n ,

large

d e c r e a s e of a c t i v i t y , 8

p o t e n c y of [ D - L y s , further

a s d i d o m i s s i o n of t h e G l y 9

Phe ]ACTH-(7-16)-NH

100-fold when L y s

1

1

2

1

0

in a

residue (11).

w a s r e p l a c e d by D - L y s

1

1

. A n additional

1 0 - f o l d i n c r e a s e in p o t e n c y w a s o b s e r v e d after N - t e r m i n a l of t h e l a t t e r a n a l o g u e w i t h M e t ( 0 2 ) - G l u - H i s ;

The

was increased a

elongation

the new peptide

100,000 times as active as reference A C T H - ( 4 - 1 0 )

on a

was

weight



7. VAN NISPEN AND GREVEN

Activity

157

b a s i s . T h e m o s t potent a n a l o g u e reported to date i s H - M e t ( 0 2 ) - A l a -Ala-Ala-D-Lys-Phe-Gly-D-Lys-Pro-Val-Gly-Lys-Lys-NH is 3 m i l l i o n t i m e s a s active a s A C T H - ( 4 - 1 0 ) , million times on a molar

Discussion.

which

2

i . e . m o r e than 4

base.

T h e tetrapeptide

H-Met-Glu-His-Phe-OH

est sequence which w a s a s active a s A C T H - ( 1 - 3 9 ) b a s i s . Additional information

i s the short-

on a weight

for e x t i n c t i o n o f p o l e - j u m p i n g

a v o i d a n c e behaviour s e e m s to b e s t o r e d , in a latent f o r m ,

in the

A C T H m o l e c u l e in fragments 7 - 1 0 , 1 1 - 1 3 a n d 2 5 - 3 9 ( 1 1 ) . A


s i m i l a r f i n d i n g w a s reported by E b e r l e a n d S c h w y z e r for m e l a n o c y t e - s t i m u l a t i n g a c t i v i t y of a - M S H f r a g m e n t s ;

they found two d i s c r e t e

m e s s a g e s e q u e n c e s for m e l a n i n d i s p e r s i o n , i . e . t h e f r a g m e n t s and 1 1 - 1 3 - N H

2

4-10

(13) .

T h e e f f e c t s of L / D s u b s t i t u t i o n s in A C T H - ( 4 - 1 0 ) p o l e - j u m p i n g behaviour were quite different activities. While A r g

8

or ( 4 - 9 ) o n

from those on hormonal

m a y be replaced by L y s

8

without l o s s of

behavioural p o t e n c y , a d r a s t i c d e c r e a s e in s t e r o i d o g e n i c a n d lipolytic effects w a s observed when the s a m e modification w a s introduced in A C T H - ( 1 - 2 4 )

(_14). D - A r g

8

and also D - H i s

6

substitu-

t i o n s s h o w e d a n i n c r e a s e i n b e h a v i o u r a l p o t e n c y but r e s u l t e d i n i n a c t i v e c o m p o u n d s w h e n t e s t e d for m e l a n o c y t e - s t i m u l a t i n g 7

(in the 6 - 1 0 fragment)

(15).

[D-Phe ]ACTH-(6-10)

reported to b e 30 t i m e s

(15) a n d 5 - 1 0 t i m e s

the a l l - L - p e p t i d e in the latter t e s t . -NH

2

activity

has been

(16) m o r e a c t i v e 4

Ac-[Nle ,

than

7

D-Phe ]ACTH-(4-10)-

w a s 10 t i m e s a s a c t i v e a s t h e L - a n a l o g u e w h e n m e a s u r e d i n

t h e f r o g s k i n a s s a y b u t a b o u t 160 t i m e s m o r e p o t e n t i n t h e l i z a r d s k i n a s s a y ( 1 7 ) . A n increase in potency w a s a l s o observed in the m o u s e m e l a n o m a a d e n y l a t e c y c l a s e a s s a y ( 1 7 ) . In t h e p o l e -jumping test,

only the L - / D - P h e

7

replacement resulted in a

r e v e r s a l of a c t i o n i . e . a c c e l e r a t i o n i n s t e a d of d e l a y of e x t i n c t i o n . 5

8

[D-Glu ,

Lys ] ACTH-(4-9)

w a s slightly more a c t i v e than the a l l -

- L - p e p t i d e in the p o l e - j u m p i n g t e s t . 5

activity,

[D-Glu ]ACTH-(4-10)

its L - G l u

5

W h e n t e s t e d for l i p o l y t i c

p o s s e s s e d o n l y 2% o f t h e a c t i v i t y of

analogue (18) . T h e s e results c l e a r l y indicated a d i s -

s o c i a t i o n b e t w e e n r e q u i r e m e n t s for b e h a v i o u r a l a c t i v i t y o n t h e o n e hand and m e l a n o c y t e - s t i m u l a t i n g Further e v i d e n c e for t h i s s t a t e m e n t substitutions

or l i p o l y t i c a c t i v i t i e s o n t h e o t h e r . c a m e f r o m d a t a of other

: o x i d a t i o n of t h e M e t r e s i d u e i n A C T H or

a-MSH

r e s u l t e d i n a m a r k e d d e c r e a s e of c o r t i c o t r o p i c ( 1 9 ) a n d m e l a n o c y t e -stimulating

( 2 0 ) a c t i v i t y but to m o r e a c t i v e c o m p o u n d s i n t h e 9

b e h a v i o u r a l a s s a y . T r p , a l s o important for the c o r t i c o t r o p i c


158

CONFORMATIONALLY DIRECTED DRUG DESIGN (2M, 2 2 ) ,

a c t i v i t y of A C T H

c a n n o t be r e p l a c e d by P h e without a

m a r k e d l o s s of s t e r o i d o g e n i c p o t e n c y ; t h i s i s i n c o n t r a s t t o a potentiation in the p o l e - j u m p i n g

T h e i n t r o d u c t i o n of a D - L y s i n p o s i t i o n 8 in A C T H - ( 4 - 9 ) in a 10-30

3-fold

test.

fold increase in p o l e - j u m p i n g a c t i v i t y ,

i n c r e a s e of t h e L / D s u b s t i t u t i o n s ; i n t e r e s t i n g l y ,

resulted

b y far the D-Arg

8

largest

gave only a

3 - f o l d p o t e n t i a t i o n . S i n c e the s a m e m e t a b o l i c s t a b i l i z a t i o n m a y

be

e x p e c t e d for t h o s e t w o c o m p o u n d s , t h e h i g h e r p o t e n c y for t h e D - L y s a n a l o g u e m i g h t be attributed to an i n c r e a s e in receptor a f f i n i t y .

It

w a s s u g g e s t e d b y G r e v e n a n d d e W i e d t h a t t h e f l e x i b l e s i d e - c h a i n of


the D - L y s r e s i d u e c a n f u n c t i o n m o r e e f f i c i e n t l y a s an e l e c t r o s t a t i c a n c h o r at the r e c e p t o r s i t e t h a n the m o r e b u l k y a n d r i g i d D - A r g s i d e - c h a i n (23)

8

.

B i o l o g i c a l a n d p h y s i c o - c h e m i c a l p r o p e r t i e s of A C T H - ( 4 - 1 0 )

and

Org 2766

B i o l o g i c a l a c t i v i t i e s in a n i m a l s .

In o r d e r t o s e e h o w t h e

i n c r e a s e i n p o t e n c y of t h e m o d i f i e d h e x a p e p t i d e -His-Phe-D-Lys-Phe-OH,

1000-fold

H-Met(C )-Glu2

c o d e d O r g 2 7 6 6 , to d e l a y e x t i n c t i o n of

p o l e - j u m p i n g behaviour w a s r e l a t e d to its e n d o c r i n e a c t i v i t i e s ,

the

effects on corticotropic, lipotropic and m e l a n o c y t e - s t i m u l a t i n g a c t i v i t y w e r e c o m p a r e d w i t h t h o s e of A C T H - ( 4 - 1 0 ) .

O n l y 1% or l e s s

of t h e s e m e n t i o n e d a c t i v i t i e s w a s p r e s e n t ( T a b l e I ) .

Studies

comparing A C T H - ( 4 - 1 0 )

a n d O r g 2766 in other

(behavioural)

situations c l e a r l y s h o w e d different structure-activity (Table I).

test

relationships

In m o s t c a s e s a c l e a r d i f f e r e n c e i n p o t e n c y ( O r g 2 7 6 6

being m o r e potent) and in s o m e c a s e s e v e n a r e v e r s e d a c t i o n w a s found (social interaction);

w h e n t e s t e d for g r o o m i n g b e h a v i o u r ,

peptides showed no effect.

R e c e n t s t u d i e s of F e k e t e a n d d e W i e d

s h o w e d t h a t O r g 2 7 6 6 h a d a l o n g e r t i m e c o u r s e of a c t i o n i n t h e and p a s s i v e a v o i d a n c e tests than A C T H - ( 4 - 1 0 ) administration (24).

both

active

after s u b c u t a n e o u s

In t h e s e l a t t e r t w o t e s t s , O r g 2 7 6 6 w a s a l s o

found to be a c t i v e after oral a d m i n i s t r a t i o n 1 0 / 4 g / k g s h o w e d oral a c t i v i t y

( a d o s e of a p p r o x .

in the a c t i v e a v o i d a n c e t e s t ;

- ( 4 - 1 0 ) w a s not a c t i v e w h e n g i v e n o r a l l y ) .

ACTH-

When dose-response

r e l a t i o n s h i p s were s t u d i e d after i n t r a c e r e b r o v e n t r i c u l a r ,

subcuta-

n e o u s a n d o r a l a d m i n i s t r a t i o n of t h e s e t w o p e p t i d e s a n d t h e s u p e r active H - M e t ( 0 ) - A l a - A l a - P h e - D - L y s - P h e - G l y - D - L y s - P r o - V a l 2

-Gly-Lys-Lys-NH

2

[1,000,000 times as active as A C T H - ( 4 - 1 0 ) 1

a weight b a s i s ] , the relative potency r a t i o s r e m a i n e d fairly

s t a n t i r r e s p e c t i v e of t h e r o u t e of a p p l i c a t i o n ( 2 3 ) . T h i s i n d i c a t e s


on

con-

7.



T a b l e I.

159

C o m p a r i s o n of a c t i v i t i e s of O r g 2 7 6 6 a n d t h e r e f e r e n c e peptide A C T H - ( 4 - 1 0 )

Activity

9

in r a t s .

Ref.

Org 2766

ACTH-(4-10)

25

1

0.01

1

0.01

i

Melanocyte-stimulating (lizard)

1

0.001

i

Pole-jumping

1

1000°

10

Passive avoidance

1

1000°

24

1

1000

d

26

1

100

27

no

28

Corticotropic (cell

s u s p e n s i o ni)

Lipolytic (in vitro,


Activity

rabbits)

c

(pre-retention ) A t t e n u a t i o n of C 0 2 ~ i n d u c e d amnesia Acquisition (hypox.

shuttle-box rats)

A f f i n i t y for o p i a t e r e c e p t o r Groom ing Social

yes,

weak

decrease;

interaction^

increase;

1

S t r e s s - i n d u c e d motor

stimulation

membrane

p h o s p h o r y I at i o n

33

stimulation

34

n

1

35

i n a c t i v e in

36

1

regeneration

i b i d , in a d r e n a l e c t o m i z e d

active 4-10

ng

these doses

rats

b.

active

inactive

0

a.

32

in activity

activity

Axonal nerve

31

prevents decline

inactive

Analeptic *

Synaptic

30

1000

1000

1

Self-stimulation*

29

inactive

inactive

e

Subcutaneous administration unless stated otherwise. E f f e c t w a s of longer d u r a t i o n . A l s o a c t i v e after oral

administra-

tion. c.

Post-trial

d.

A l s o a c t i v e after oral

: ACTH-(4-10)

no effect,

Org 2766

effective.

administration.

e.

Intraventricular

f.

A d m i n i s t r a t i o n in s e p t u m .

g.

R e v e r s i n g pentobarbital-induced s e d a t i o n ; intraperitoneal intracisternal

administration.

and

administration.

h.

S t i m u l a t i o n of d i p h o s p h o i n o s i t i d e ( D P I )

i.

Unpubl i shed data.

formation,

in v i t r o .


160


that the c o m b i n a t i o n of m e t a b o l i c s t a b i l i t y

a n d transport

characteris-

t i c s i s about t h e s a m e for t h e three p e p t i d e s , a n d s u g g e s t s that t h e i n c r e a s e i n p o t e n c y for t h e t w o a n a l o g u e s of A C T H - ( 4 - 1 0 ) d u e to a n i n c r e a s e d a f f i n i t y for the r e l e v a n t

S t u d i e s in m a n . T h e a n i m a l

receptor

is mainly

site.

studies with A C T H - ( 4 - 1 0 )

and Org

2 7 6 6 h a v e s u g g e s t e d t h a t t h e s e p e p t i d e s e n h a n c e a t t e n t i o n or m o t i v a t i o n a n d that they a l s o m a y i m p r o v e m e m o r y

consolidation

( for a r e v i e w s e e 3 7 ) . S t u d i e s u s i n g a c u t e s y s t e m i c

administration

of A C T H - ( 4 - 1 0 )

intravenously)

(subcutaneously,

intramuscularly

or


i n d i c a t e d i n c r e a s e d s e l e c t i v e a t t e n t i o n a n d or m o t i v a t i o n volunteers and in patients -(4-10)

(38, 3 9 ) . Inconsistent

both in

e f f e c t s of A C T H -

o n t e s t s of m e m o r y a n d o t h e r t e s t s of c o g n i t i v e

performance

h a v e b e e n f o u n d ( 3 8 ) . S u b c u t a n e o u s or o r a l a d m i n i s t r a t i o n 2766 (acute studies) 39).

of O r g

have l e d to e s s e n t i a l l y the s a m e r e s u l t s

T h e s e p e p t i d e s differ f r o m

(38,

(other) p s y c h o s t i m u l a n t drugs in

that they d o not s h o w a n y u n w a n t e d

side-effects.

R e c e n t f i n d i n g s after s u b c h r o n i c , oral a d m i n i s t r a t i o n

of O r g 2 7 6 6

in d a i l y d o s e s of 1 0 - 4 0 m g , s h o w e d a d e c r e a s e i n a n x i e t y a n d depression (self-rated) and an improvement tence,

sociability and ward behaviour

of f e e l i n g s o f c o m p e -

(observer-rated)

(39) . N o

side-effects like influence on autonomic activity and appetite, no sedative effects were reported.

and

It s e e m s t h a t O r g 2 7 6 6 m a y b e a

drug to b e u s e d i n t r e a t i n g d i s t u r b a n c e s of m o o d i n the e l d e r l y a s w e l l a s s y m p t o m s of d e m e n t i a .

Many studies in these areas are

underway.

P h y s i c o - c h e m i c a l properties.

In t h e f i f t i e s a n d s i x t i e s ,

several

s t u d i e s o n t h e c o n f o r m a t i o n of A C T H i n s o l u t i o n w e r e c a r r i e d o u t . A m o n g the u s e d techniques were O R D , C D , f l u o r e s c e n c e d e p o l a r i z a t i o n s t u d i e s a n d k i n e t i c s of d e u t e r i u m h y d r o g e n e x c h a n g e (for a review s e e r e f . 2 ) . T h e results pointed to a highly flexible coil in s o l u t i o n ; however, between T y r

2

and T r p

9

[ i n A C T H - ( 1 - 2 4 ) ] a s m e a s u r e d by e x c i t a t i o n

s p e c t r o s c o p y , w a s i n better a g r e e m e n t helical structure. helical content,

w i t h s o m e f o r m o f l o o p or

In a d d i t i o n , S q u i r e a n d B e w l e y n o t e d located in the N - t e r m i n a l

and acidic pH values,

P r e d i c t i o n of t h e s e c o n d a r y s t r u c t u r e

11-15%

1-11 p a r t o f t h e m o l e c u l e ,

w h e n m e a s u r i n g t h e O R D o f A C T H at p H 8 . 1 w a s f o u n d at n e u t r a l

random

E i s i n g e r (40) f o u n d that the d i s t a n c e

(41)

(a random coil

2).

of A C T H u s i n g t h e r u l e s of

C h o u a n d F a s m a n (42) by L o w et a l . ( 4 3 ) ,

J i b s o n a n d Li (44) and

M u t t e r et a l . ( 4 5 ) , r e v e a l e d a p r e f e r e n c e for a n a - h e l i c a l

structure


7.



Activity

f o r t h e f r a g m e n t s 3 - 9 ( 4 3 ) or 2 - 9 ( 4 4 , 4 5 ) a n d 2 7 - 3 5

161

( 4 3 , 4 4 ) or

2 9 - 3 4 ( 4 5 ) a n d i n d i c a t i o n s f o r a (3-turn at 2 3 - 2 6 ( 4 3 , 4 4 , 4 5 ) a n d f

12-15

( 4 4 ) or 1 4 - 1 7 ( 4 5 ) . A p p l y i n g T a n a k a a n d S c h e r a g a s m e t h o d

( 4 6 ) , M u t t e r et a l . c a l c u l a t e d t h e a - h e l i c a l r e g i o n to b e f r a g m e n t 2-9

(45). In t h e m i d - s e v e n t i e s , L o w e t a l . s t u d y i n g A C T H - ( 1 - 3 9 )

fragments,

found a transition from random coil to a helix

and

structure

when the s o l v e n t water w a s gradually r e p l a c e d by trifluoroethanol (TFE)

( 4 3 ) . T h i s latter s o l v e n t h a d b e e n s h o w n t o favour the

e s t a b l i s h m e n t of o r d e r e d s t r u c t u r e s ( ( 3 - s h e e t or a - h e l i x )


membrane-receptor properties)

environment

("membrane-receptor

like a mimetic"

( 4 7 ) . S u b s e q u e n t w o r k of t h e g r o u p s of L o w a n d

Fermandjian on A C T H - ( 1 - 3 9 ) a n a l o g u e s m a k i n g u s e of

1

a n d several large fragments a n d

H - and 13C - N M R

s p e c t r o s c o p y , IR

h y d r o g e n - d e u t e r i u m e x c h a n g e k i n e t i c s a n d C D a l l p o i n t e d to h e l i c a l s t r u c t u r e s of s e q u e n c e s i n A C T H

(48, 49 and references

S m a l l A C T H f r a g m e n t s related to A C T H - ( 4 - 1 0 )

therein).

have also been

i n v e s t i g a t e d for the p r e s e n c e of o r d e r e d s t r u c t u r e . C D of A C T H -(5-10) 1

in T F E showed a random structure

H-NMR

for f r a g m e n t

(50) a s w a s found with

4 - 1 0 ( 5 1 ) . T h e a d d i t i o n o f a n i o n i c or c a t i o n i c

s u r f a c t a n t s to a n a q u e o u s s o l u t i o n of A C T H - ( 4 - 1 1 ) a n y a - h e l i x or (3-fornn i n t h i s p e p t i d e ACTH-(1-14)

d i t not p r o m o t e

( C D experiments;

52).

When

a n d 1-10 were m e a s u r e d by C D a n d N M R r e s p e c t i v e l y ,

i n d i c a t i o n s f o r a h e l i c a l or o r d e r e d s t r u c t u r e w e r e f o u n d ( 5 0 , T h u s it s e e m s t h a t t h e a d d i t i o n o f t h e n o n - h e l i x " p r o n e "

51).

fragment

1 - 3 or 1 - 4 c a n p r o m o t e t h e f o r m a t i o n o f a h e l i c a l s t r u c t u r e i n t h e a d j a c e n t s e q u e n c e . A r g u m e n t s i n favour of t h i s c o m e f r o m the t h e o r e t i c a l work of A r g o s a n d P a l a u (53) o n a m i n o a c i d d i s t r i b u t i o n in protein s e c o n d a r y s t r u c t u r e s . They found that S e r a n d Thr frequently o c c u r at t h e N - t e r m i n a l h e l i c a l p o s i t i o n ( c f . S e r ACTH)

to provide s t a b i l i t y ;

1

0

);

to T r p

9

in

a c i d i c a m i n o a c i d residues are frequently

found at the h e l i x N - t e r m i n u s r e s i d u e s at t h e C - t e r m i n u s Crystal structure(s)

in

the position adjacent to the helical

C - t e r m i n u s i s o f t e n o c c u p i e d b y G l y or P r o ( a d j a c e n t A C T H we have G l y

3

(cf. G l u

(cf.

5

in A C T H ) and/or basic

8

Arg ).

of A C T H - ( 1 - 3 9 )

or 1 - 2 4 a r e n o t k n o w n .

S u i t a b l e c r y s t a l s for X - r a y d i f f r a c t i o n e x p e r i m e n t s c o u l d b e obtained however,

for t h e h e p t a p e p t i d e 4 - 1 0 ( 5 4 , 55) a n d the

s m a l l e r tetrapeptide -parallel

4 - 7 ( 5 4 , 5 6 ) . In t h e f o r m e r c a s e ,

an anti-

( 3 - p l e a t e d s h e e t s t r u c t u r e of t h e b a c k b o n e w a s f o u n d w i t h

c l u s t e r i n g of h y d r o p h o b i c ( M e t , P h e a n d T r p ) a n d h y d r o p h i l i c ( G l u , His,

Arg) side-chains as remarkable features.

ACTH-(4-7)


162


c r y s t a l l i z e s as a monohydrate horseshoe-1 ike structure w h i c h is a g a i n c h a r a c t e r i z e d b y t h e p r o x i m i t y of t h e h y d r o p h o b i c P h e a n d a n d t h e h y d r o p h i l i c G l u a n d H i s r e s i d u e s , but n o w v i a i n t r a i n t e r - c h a i n i n t e r a c t i o n s . S o in two quite different s t r u c t u r e s of A C T H - ( 4 - 1 0 )

conformational

and 4-7 a striking c o m m o n feature is

that the P h e a n d M e t s i d e - c h a i n s are c l o s e t o g e t h e r .

Org 2766 has

n o t y e t y i e l d e d c r y s t a l s s u i t a b l e e n o u g h for s t r u c t u r e

determination.

In s u m m a r y ,

theoretical

a p p r o a c h e s point to the p o t e n t i a l

a n a - h e l i c a l s t r u c t u r e for t h e f r a g m e n t 4 - 1 0

and the

for

conformation

f o u n d i n s o l u t i o n s of t h i s a n d s e v e r a l o t h e r f r a g m e n t s of A C T H to be c o n f i r m a t o r y ;


Met

and

the c r y s t a l structure r e v e a l s a n

seem

antiparallel

[3-pleated s h e e t .

S u g g e s t i o n for c o n f o r m a t i o n at t h e r e c e p t o r s i t e for

pole-jumping

activity

In 1977 a q u a n t i t a t i v e s t u d y o n t h e r e l a t i o n s h i p b e t w e e n t h e

structure

a n d p o l e - j u m p i n g b e h a v i o u r of A C T H - d e r i v e d p e p t i d e s ( o n l y

those

that d e l a y e d e x t i n c t i o n ) ,

w a s p e r f o r m e d (1_1,

57)

a c c o r d i n g to

m e t h o d of F r e e a n d W i l s o n a s m o d i f i e d b y F u j i t a a n d B a n

(58).

A p p a r e n t l y t h e d a t a o n 5 5 p e p t i d e s s a t i s f i e d t h e c o n d i t i o n s for a mathematical

such

a p p r o a c h w h i c h m e a n s t h a t t h e p o t e n c i e s of t h e

a n a l o g u e s c o u l d b e c o n s i d e r e d t o b e c o m p o s e d of t h e p r o d u c t of independent group c o n t r i b u t i o n s f r o m individual s u b s t i t u t i o n s in the p e p t i d e c h a i n . F o r i n s t a n c e , t h e c o m b i n a t i o n of D - L y s D-Glu

5

or D - H i s

However,

8

8

with either

gave the s a m e actual and c a l c u l a t e d a c t i v i t i e s .

when D - L y s

8

was c o m b i n e d with D - M e t

-Glu-His-Phe-D-Lys-Trp-OH,

4

a s in

the o b s e r v e d potency w a s

H-D-Metmuch

l o w e r t h a n t h e c a l c u l a t e d o n e . S i n c e t h i s i s o n e of t h e v e r y e x c e p t i o n s where the c a l c u l a t i o n f a i l e d ,

i.e.

independent group c o n t r i b u t i o n s w a s no longer f u l f i l l e d w a s s u g g e s t e d by G r e v e n a n d de W i e d (11) s t e r i c i n t e r f e r e n c e of t h e D - M e t

4

few

t h e c o n d i t i o n of (outlier),

it

that t h i s c o u l d be d u e to

and D - L y s

8

residues, which

in

t u r n i m p l i e s t h a t p o s i t i o n s 4 a n d 8 a r e c l o s e t o g e t h e r at t h e r e c e p t o r s i t e . T h e a m i n o a c i d s in b e t w e e n s e e m to s e r v e m e r e l y a s a s p a c e r a s w a s s h o w n b y r e p l a c e m e n t of t h e s e a m i n o a c i d s b y s i m p l e , neutral a l a n i n e r e s i d u e s ( 1 1 ) .

T h i s c l o s e p r o x i m i t y of t h e s i d e -

- c h a i n s of r e s i d u e s 4 a n d 8 i s p o s s i b l e w h e n t h e b a c k b o n e a s s u m e s an a - h e l i c a l conformation ( 1 1 ) . and P h e

7

In t h i s h e l i c a l s t r u c t u r e t h e

Met

4

r e s i d u e s are e x t r a - c h a i n n e i g h b o u r s .

T h e (3-lipotropin fragments H - T y r - G l y - G l y - P h e - M e t - O H -enkephalin)

(Met-

a n d H - G l y - G l y - P h e - M e t - O H s h o w t h e p r e s e n c e of P h e


7.


VAN NISPEN A N D G R E V E N

Activity

163

and M e t a s i n t r a - c h a i n n e i g h b o u r s . W h e n these two m o l e c u l e s were t e s t e d for d e l a y of e x t i n c t i o n i n the p o l e - j u m p i n g t e s t , f o u n d to b e a p p r o x . a s a c t i v e a s A C T H - ( 4 - 1 0 )

(23,

they were

9).

In a d d i t i o n ,

o x i d a t i o n of M e t t o M e t ( O ) r e s u l t e d i n a s i m i l a r p o t e n t i a t i o n a s t h a t f o u n d i n the A C T H s e r i e s . T h e h y p o t h e s i s that the c l o s e p r o x i m i t y of a P h e and M e t r e s i d u e in A C T H - and enkephalin-1 ike p e p t i d e s i s e s s e n t i a l for a d e l a y i n e x t i n c t i o n w a s f u r t h e r c h e c k e d b y t e s t i n g a c y c l i c peptide containing P h e , Met and a spacer e-aminohexanoic a c i d O s A h x ) t o c l o s e t h e r i n g [ s A h x w a s c h o s e n s i n c e it c o n t a i n s


no f u n c t i o n a l g r o u p s a n d d o e s not d i s t o r t the p e p t i d e g r o u p s s i g n i f i c a n t l y f r o m p l a n a r i t y or f o r c e t h e m i n t o t h e c i s c o n f o r m a t i o n

(59)].

Cyclo-(-Phe-Met-gAhx-)

ACTH-

-(4-10)

(60)

w a s f o u n d to be a s a c t i v e a s

in d e l a y i n g extinction ( 9 ) ,

of G r e v e n a n d d e W i e d

thus supporting the h y p o t h e s i s

(11).

A s mentioned before ( s e c t i o n 1 ) , r e s i d u e in the A C T H f r a g m e n t 4 - 1 0

i n t r o d u c t i o n of t h e D - L y s

or 4 - 9 r e s u l t e d i n a h i g h e r

i n c r e a s e in a c t i v e a v o i d a n c e behaviour than the 3 - f o l d i n c r e a s e in a c t i v i t y w h e n L - A r g w a s r e p l a c e d by D - A r g , s u g g e s t i n g an a d d i t i o n a l f u n c t i o n of t h e D - L y s r e s i d u e at t h e r e c e p t o r s i t e . T h e m e r e p r e s e n c e of D - L y s , M e t ( O )

or M e t ( 0 ) 2

and P h e in one m o l e c u l e a s in Org

2 7 6 6 i s n o t s u f f i c i e n t , h o w e v e r , for h i g h a c t i v i t y

in the

pole-jumping

test. When H - G l y - G l y - P h e - M e t ( O ) - D - L y s - P h e - O H was tested, a c c e l e r a t i o n i n s t e a d of d e l a y o f e x t i n c t i o n w a s f o u n d . T h e corresponding a l l - L hexapeptide delayed extinction and was as active as A C T H - ( 4 - 1 0 )

(Greven and de W i e d , unpublished results) . A

s p e c i a l s p a t i a l a r r a n g e m e n t of t h e s e t h r e e r e s i d u e s at t h e r e c e p t o r for p o l e - j u m p i n g a c t i v i t y t h e r e f o r e a p p e a r s t o b e a r e q u i r e m e n t high activity

for

i n d e l a y i n g e x t i n c t i o n of a c o n d i t i o n e d a v o i d a n c e

response. S u g g e s t e d preferred c o n f o r m a t i o n s c a n be f i x e d by c y c l i z a t i o n . C y s t i n e h a s b e e n u s e d to o b t a i n c y c l i c a n a l o g u e s of O r g 2 7 6 6 v i z . H-Cys-Glu-His-Cys-D-Lys-Phe-OH,

H-Cys-Ala-Ala-"Cys-D-Lys-

- P h e - O H and H - C y s - A l a - A l a - P h e - D - L y s - C y s - O H

(patent a p p l i c a -

t i o n 0 0 5 2 0 2 8 of R o u s s e l - U c l a f ) , a n d t h e p e p t i d e s w e r e t e s t e d for activity

in the p o l e - j u m p i n g t e s t .

Unfortunately,

one cannot

con-

c l u d e f r o m t h e i r d a t a if c y c l i z a t i o n h a s r e s u l t e d i n a n i n c r e a s e or d e c r e a s e in a c t i v i t y s i n c e no r e f e r e n c e p e p t i d e h a s b e e n i n c l u d e d to 5

c o m p a r e p o t e n c i e s . In t h e l i t e r a t u r e c y c l i z a t i o n o f [ L y s ] A C T H -(5-10)

(the C O O H g r o u p of G l y

1

0

with the £ - N H

5

2

f u n c t i o n of L y s )

h a s been reported; the r e s u l t i n g peptide w a s i n a c t i v e in s t e r o i d o g e n e s i s ( 6 1 ) . I n c r e a s e of t h e r i n g s i z e w i t h t h r e e a t o m s G l y r e s i d u e ) , h o w e v e r , r e s u l t e d in a p e p t i d e that w a s m o r e


(a

active

164


than the linear u n m o d i f i e d 5 - 1 0

s e q u e n c e (61.)

indicating

s

the

i m p o r t a n c e of t h e r i n g s i z e . C y c l i z a t i o n of t h e m e s s a g e s e q u e n c e for s t e r o i d o g e n i c a c t i v i t y b y r e p l a c e m e n t of G l u c y s t i n e residue in [ 2 - $ - a m i n o v a l e r i c

5

and G l y ^ by a

acid]ACTH-(2-19)

r e s u l t e d in

a 5 0 - f o l d d e c r e a s e in steroidogenic activity and 10-fold d e c r e a s e in lipolytic activity

(62).

When a cystine molecule was

i n t o a - M S H i n p l a c e of M e t

4

and G l y

1

0

incorporated

, a very potent a n a l o g u e w a s

o b t a i n e d w i t h a p o t e n c y > 1 0 , 0 0 0 t i m e s t h a t of a - M S H i n frog s k i n d a r k e n i n g a n d about 30 t i m e s m o r e potent w h e n in vitro in lizard s k i n

stimulating measured

(63).


T h u s s t r o n g p o t e n t i a t i o n of b i o l o g i c a l a c t i v i t y c a n b e o b t a i n e d e i t h e r b y s u b s t i t u t i o n s w h i c h a l l o w or e n h a n c e a p r e f e r r e d c o n f o r m a t i o n at t h e r e c e p t o r s i t e or b y f i x a t i o n o f s u c h a p r e f e r r e d c o n f o r m a t i o n v i a c y c l i z a t i o n of t h e b a c k b o n e .

Concluding

remarks

F o r a c t i v i t y of A C T H - d e r i v e d p e p t i d e s at t h e r e c e p t o r for ing a c t i v i t y ,

the b a s i c requirement

P h e and M e t r e s i d u e in c l o s e p r o x i m i t y . P h e and M e t are c l o s e together

pole-jump-

s e e m s to b e the p r e s e n c e of a It i s i n t e r e s t i n g t o s e e t h a t

in an a - h e l i c a l structure in A C T H

p e p t i d e s ( a n d a s i n t r a - c h a i n n e i g h b o u r s in M e t - e n k e p h a l i n ) the c r y s t a l l i n e state in A C T H - ( 4 - 1 0 ) ACTH-(4-7)

and in

a s a [3-pleated sheet a n d in

i n t h e f o r m of a h o r s e s h o e ; t h i s c l o s e p r o x i m i t y

is in

l i n e w i t h t h e r e s u l t s of a F r e e - W i l s o n t y p e of a n a l y s i s . In H - M e t ( C ) - G l u - H i s - P h e - D - L y s - P h e - O H ( O r g 2 7 6 6 ) , 2

large i n c r e a s e in activity

in the p o l e - j u m p i n g test a n d the

the

longer

d u r a t i o n of a c t i o n c a n o n l y p a r t l y b e e x p l a i n e d b y a n i n c r e a s e i n stability.

It i s s u g g e s t e d t h a t i n t h e f o r m of a n a - h e l i x or l o o p - 1 i k e

s t r u c t u r e at t h e r e c e p t o r s i t e , Met(0 ) 2

4

and P h e

9

t h e p r e s e n c e of D - L y s

3

as well

c o n t r i b u t e s t o a n i n c r e a s e of r e c e p t o r

as

affinity.

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15, 1983


Structure-Behavioral Activity Relationships of Peptides Derived from

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