Aspects of the Biochemistry and Toxicology of Octopamine in Arthropods

7 Aspects of the Biochemistry and Toxicology of Octopamine in Arthropods R. M. HOLLINGWORTH, Ε. M. JOHNSTONE, and N. WRIGHT

Downloaded by CORNELL UNIV on September 3, 2016 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch007

Department of Entomology, Purdue University, West Lafayette, IN 47907

The occurrence, physiological significance, and biochemistry of octopamine (1-[4-hydroxyphenyl]-2aminoethanol; OA) in arthropods are reviewed with emphasis on the applications of this information to the discovery of new pesticides. The functions of OA in arthropods parallel those of norepinephrine in vertebrates, with probable involvement in stress responses, arousal, and feeding. The best current prospect to disrupt these functions is to design compounds that affect octopamine receptors. Recent results on the structure-activity relations (SAR) of three groups of OA agonists, phenylethylamines, amidines, and imidazolines are presented. These cause symptoms in arthropods congruent with stimulatory actions on OA receptors. A variety of OA antagonists are known, but the data are currently insufficient for SAR analysis or to indicate whether such compounds may be useful for the control of arthropods in the f i e l d .

Prominent among the approaches t o p e s t i c i d e d i s c o v e r y which can l e g i t i m a t e l y be termed r a t i o n a l i s b i o c h e m i c a l l y - a i d e d design. This approach i s based on the thoughtful s e l e c t i o n o f a biochemical t a r g e t s i t e i n a group o f important p e s t s , the study o f i t s p r o p e r t i e s , and the s y n t h e s i s o f compounds which might be capable of i n t e r f e r i n g with i t s normal f u n c t i o n s . Such an approach i s i n c r e a s i n g l y i n t e r e s t i n g , not because o f i t s inherent high p r o b a b i l i t y o f success or ease o f p u r s u i t , but because o f the decreasing e f f i c i e n c y o f t r a d i t i o n a l s y n t h e s i s and screening approaches, p a r t i c u l a r l y i n the area o f arthropod c o n t r o l agents (1-3)t and the i n c r e a s i n g s o p h i s t i c a t i o n o f our knowledge o f pest physiology and b i o c h e m i s t r y .

0097-6156/84/0255-0103S06.75/0 © 1984 American Chemical Society

Magee et al.; Pesticide Synthesis Through Rational Approaches ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

104

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

Desirable

Characteristics

of

a

Biochemical

Target

Some o f t h e m o s t i m p o r t a n t c o n s i d e r a t i o n s i n s e l e c t i n g a t a r g e t a b i o c h e m i c a l l y - a i d e d design program are presented i n Table I .


Table

I.

Important

Criteria

in

Choosing a Biochemical

Target

1.

T a r g e t i s l i k e l y t o be e s s e n t i a l f o r t h e more e c o n o m i c a l l y i m p o r t a n t species.

2. 3. 4.

Target has been 'validated . Rapid response to d i s r u p t i o n o f t a r g e t i s p r e d i c t e d . High p o t e n t i a l for s e l e c t i v i t y / l o w vertebrate t o x i c i t y .

5. 6.

Low p o t e n t i a l f o r resistance. Compounds a r e known w h i c h c a n a f f e c t t h e t a r g e t and a c t as l e a d s f o r new s y n t h e s i s . P h a r m a c o k i n e t i c s o f l e a d compounds are favorable. C o n v e n i e n t a s s a y s f o r i n v i t r o and i n v i v o a c t i v i t y e x i s t . Background b i o c h e m i s t r y and p h y s i o l o g y o f t a r g e t system i s reasonably well understood. Concept i s n o v e l .

7. 8. 9. 10.

survival

for

o f one

or

1

A l l these requirements are d e s i r a b l e i n a proposed t a r g e t , but n o t a l l a r e c r i t i c a l . Some a r e c e r t a i n l y m o r e i m p o r t a n t t h a n o t h e r s , and no t a r g e t s y s t e m i s l i k e l y t o s a t i s f y a l l o f t h e m . Most are s e l f - e v i d e n t , but o t h e r s deserve a word o f e x p l i c a t i o n . In regard to item 2, a ' v a l i d a t e d t a r g e t i s one where t h e r e i s d i r e c t or good i n d i r e c t e v i d e n c e t h a t i f compounds are found t h a t can d i s r u p t the t a r g e t , they w i l l have a potent p h y s i o l o g i c a l e f f e c t w h i c h can be t r a n s l a t e d i n t o e f f e c t i v e a r t h r o p o d c o n t r o l under f i e l d c o n d i t i o n s . T h e s e e f f e c t s may k i l l t h e i n s e c t o r o t h e r a r t h r o p o d d i r e c t l y ( i n s e c t i c i d e s ) o r may p r e v e n t damage b y i n d u c i n g n o n - l e t h a l e f f e c t s such as a l t e r e d b e h a v i o r ( i n s e c t i s t a t s ) . For e x a m p l e , compounds w h i c h i n h i b i t a c e t y l c h o l i n e s t e r a s e c e r t a i n l y a c t o n a v a l i d a t e d t a r g e t , a l t h o u g h t h e y may b e s u b j e c t t o e x c e s s i v e r e s i s t a n c e p r o b l e m s , l a c k i n t r i n s i c s e l e c t i v i t y , and t h i s i s n o t a n o v e l t a r g e t . On t h e o t h e r h a n d i t i s p o s s i b l e t o d e s i g n i n h i b i t o r s f o r t h e enzyme w h i c h s y n t h e s i z e s a c e t y l c h o l i n e , c h o l i n e a c e t y l transferase, but i t i s not c l e a r that such i n h i b i t o r s would y i e l d s u c c e s s f u l c o n t r o l a g e n t s . I n f a c t t h e r e i s e v i d e n c e t h a t t h e y may n o t (Jp ; c h o l i n e a c e t y l t r a n s f e r a s e i s a t a r g e t which has not yet been v a l i d a t e d . 1

The need f o r l e a d compounds ( i t e m 6) i s a p a r t i c u l a r l y c r i t i c a l one s i n c e our a b i l i t y t o d e s i g n compounds t o a f f e c t e n z y m e s , rec e p t o r s , o r o t h e r b i o c h e m i c a l t a r g e t s ab i n i t i o i s v e r y l i m i t e d . H o w e v e r , t h e r e i s an i m p o r t a n t c o n s t r a i n t i n r e s p e c t t o t h e p h y s i c a l p r o p e r t i e s o f l e a d c o m p o u n d s . The n e e d f o r f a v o r a b l e p h a r m a c o k i n e t i c s ( i t e m 7 ) i s a f a c t o r w h i c h may b e o v e r l o o k e d .


7.

HOLLINGWORTH ET AL.

Octopamine in Arthropods

105

S i m p l y p u t , p o t e n t i a l t o x i c a n t s must be a b l e t o get t o the t a r g e t s i t e w i t h i n t h e i n s e c t . The i n s e c t i n t e g u m e n t i s g e n e r a l l y impermeable t o p o l a r compounds. I f compounds must a c t w i t h i n the c e n t r a l nervous system (CNS) there are a d d i t i o n a l penetration b a r r i e r s t h a t e x c l u d e c h a r g e d and h i g h l y p o l a r compounds from t h e synaptic areas i n the n e u r o p i l e . It i s therefore important i n c h o o s i n g a t a r g e t t o c o n s i d e r w h e t h e r l e a d compounds a r e known t h a t w i l l penetrate to the s i t e o f a c t i o n . There are s e v e r a l examples where the l a c k o f such f a v o r a b l e l e a d s has impeded p r o g r e s s i n discovering effective control agents. One o f t h e s e i s g l u t a m a t e as the e x c i t a t o r y t r a n s m i t t e r at the i n s e c t neuromuscular j u n c t i o n . A c t i v e compounds so f a r have c o n t a i n e d a t l e a s t t h r e e p o l a r groups a n d f e w h a v e shown h i g h p o t e n c y (5^). F u r t h e r c o n s i d e r a t i o n o f t h e d e s i r a b i l i t y , s t r a t e g i e s and p r o b l e m s a s s o c i a t e d w i t h t h e b i o c h e m i c a l d e s i g n o f p e s t i c i d e s w i l l b e f o u n d i n r e f e r e n c e s 2^3,J5 a n d 2·


f

It i s the purpose o f t h i s chapter to o c t o p a m i n e , and i t s r e l a t e d b i o c h e m i s t r y system as a t a r g e t area f o r the r a t i o n a l agents i n the l i g h t of the c r i t e r i a l i s t e The O c c u r r e n c e

of

Octopamine

in

discuss the neuroeffector, i n the arthropod nervous discovery of control d i n Table I.

A r t h r o p o d s and

Vertebrates

O c t o p a m i n e (OA) i s 1 - ( 4 - h y d r o x y p h e n y l ) - 2 - a m i n o e t h a n o l ( F i g u r e 1 ) . As s u c h i t i s one o f s e v e r a l b i o g e n i c a m i n e s w h i c h a r e r e g a r d e d as e s t a b l i s h e d or p o t e n t i a l neuroeffectors i n i n v e r t e b r a t e s ( 8 , 9 ) . The c l o s e r e s e m b l e n c e o f OA t o i t s c a t e c h o l a m i n e a n a l o g , norepinephrine (NE: F i g u r e 1 ) , i s n o t a b l e . N o r e p i n e p h r i n e and i t s N - m e t h y l a n a l o g , e p i n e p h r i n e ( E ) , a r e known t o h a v e a number o f i m p o r t a n t functions in vertebrates. I n t h e p e r i p h e r a l n e r v o u s s y s t e m , NE i s t h e m a j o r t r a n s m i t t e r at the sympathetic e f f e c t o r j u n c t i o n s , w h i l e i n the c e n t r a l n e r v o u s s y s t e m (CNS) i t i s b e l i e v e d t o i n f l u e n c e s u c h s t a t e s as a l e r t n e s s , h u n g e r , l e a r n i n g and memory, and e m o t i o n a l responsiveness ( 1 0 ) . E p i n e p h r i n e a c t s as a c i r c u l a t i n g hormone t h a t i n c r e a s e s b l o o d p r e s s u r e t h r o u g h c a r d i a c s t i m u l a t i o n and v a s o c o n s t r i c t i o n i n r e s p o n s e t o e x c i t a t i o n and s t r e s s . I t a l s o increase metabolic rates i n several tissues, leading to hyperglycemia, h y p e r l i p e m i a and i n c r e a s e d oxygen c o n s u m p t i o n . W h e r e a s N E i s a b u n d a n t i n t h e v e r t e b r a t e n e r v o u s s y s t e m , OA i s r e l a t i v e l y s c a r c e . The r e v e r s e i s t r u e i n i n s e c t s where NE i s t h o u g h t t o b e a b s e n t o r p r e s e n t o n l y a t l o w c o n c e n t r a t i o n (8). It h a s b e e n s u g g e s t e d ( 9 , 1 1 , 1 2 ) t h a t OA c a r r i e s o u t f u n c t i o n s i n t h e s e i n v e r t e b r a t e s w h i c h p a r a l l e l t h o s e o f NE a n d Ε i n v e r t e b r a t e s . A l t h o u g h i t i s n o t p o s s i b l e t o s a y t h a t OA h a s n o i m p o r t a n t functions in vertebrates, such f u n c t i o n s have y e t t o be e s t a b l i s h e d ( 1 3 ) » I f , a s i t n o w s e e m s , OA i s a m u c h m o r e c r i t i c a l n e u r o t r a n s m i t t e r in a r t h r o p o d s t h a n mammals, t h e r e i s r e a s o n t o hope t h a t compounds w h i c h a f f e c t o c t o p a m i n e r g i c s y s t e m s w i l l s h o w some d e g r e e o f s e l e c t i v e t o x i c i t y between i n s e c t and mammals, a l t h o u g h t h e r a t h e r s l i g h t s t r u c t u r a l d i f f e r e n c e b e t w e e n OA a n d N E i n d i c a t e s t h a t this w i n d o w f o r s e l e c t i v i t y may n o t b e a w i d e o n e .



PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

CHOHCH N

Aspects of the Biochemistry and Toxicology of Octopamine in Arthropods

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