richard young and richard a. glennon- cocaine-stimulus generalization to two new designer drugs:...

8/3/2019 Richard Young and Richard A. Glennon- Cocaine-Stimulus Generalization to Two New Designer Drugs: Methcathinon

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PharmacologyBiochemistryand Behavior,Vo l. 45, pp. 229-231 , 1993 0091-3057/93 $6.00 + .00Printed n the U.S.A . All rights reserved. Copyright1993 Pergam onPress Ltd.

R A P I D C O M M U N I C A T IO N

C o c a i n e - S t im u l u s G e n e r a liz a t io n t oT w o N e w D e s i g n e r D r u g s :

M e t h c a t h i n o n e a n d 4 - M e t h y l a m i n o r e xR I C H A R D Y O U N G A N D R I C H A R D A . G L E N N O N l

D e p a r t m e n t o f M e d i c i n a l C h e m i s t r y , S c h o o l o f P h a r m a c y , M e d i c a l C o ll e g e o f V i rg in ia ,V i r gi n ia C o m m o n w e a l t h U n i v e r si ty , R i c h m o n d , V A 2 32 9 8 -0 5 4 0

R e c e i v e d 9 N o v e m b e r 1 99 2

Y O U N G , R . A N D R . A . G L E N N O N . Cocaine-stimulus generalization to two new designer drugs: Meth cathinon e and4-methylaminorex. PHA RM AC OL BIOCH EM BEHAV 45(1) 229-231 , 1993 . - Ra ts were t ra ined to d iscr iminate 8 mg/k gcocaine from saline vehicle for the pu rpose of examining the stimulus prope rties of two novel and structura lly related drugsof abuse recen t ly conf iscated on the i l l ic i t market : (+)m ethcath ino ne and c/s(+ )4 -methylaminorex . The s t imulus p roper t ieso f these con tro l led substance ana logs were com pared wi th those o f thei r paren t compounds (+)ca th inone and am inorex ,respectively. A ll agents resulted in cocaine-stimulus ge neralizatio n with the following rank order o f potency: am inorex (ED~0value = 0 .8 #M /kg) > methcath inone (1 .9 #M /kg) > cath inone (3 .7 #M /kg) > 4 -methy laminorex (5 .2 #M /kg) > cocaine(7.6/LM/kg).Cocaine Cath inone Methcath inone Aminorex 4 -Methy laminorex

S E V E R A L c o n t r o l l e d s u b s t a n c e a n a l o g s ( i . e . , " d e s i g n e rd r u g s " ) a r e b e i n g , o r r e c e n t l y h a v e b e e n , p l a c e d i n S c h e d u l e Io f t h e C o n t r o l l e d S u b s t a n c e s A c t . I n t e r e s ti n g l y , f o u r o f t h e s ea g e n t s t h a t h a v e b e e n e n c o u n t e r e d o n t h e c l a n d e s t i n e m a r k e ta r e n o t t r u l y d e s i g n e r d r u g s ; o n e ( i . e . , c a t h i n o n e ) i s t h e a c t i v ec o n s t i t u e n t o f a s h r u b ( k h a t ; Catha edulis) t h a t h a s b e e na b u s e d f o r s e v e r a l ce n t u r ie s , a n d t h e r e m a i n d e r ( a r n i n o re x ,4 - m e t h y l a m i n o r e x , a n d t h e N - m e t h y l d e r i v a ti v e o f c a t h i n o n e )w e r e o r i g i n a l l y d e v e l o p e d a s p o t e n t i a l a n o r e c t i c a g e n t s b y t h ep h a r m a c e u t i c a l i n d u s t r y . H o w e v e r , t h e i r r e c e n t i ll i ci t a p p e a r -a n c e p r o b a b l y j u s t i f ie s t h i s d e s i g n a t io n . T h e s e a g e n t s a r es t r u c t u r a l ly r e l a te d t o a m p h e t a m i n e i n t h a t t h e y a r e p h e n y l is o -p r o p y l a m i n e d e r i v a t i v e s ; t h e y a r e a l l f u r t h e r r e l a t e d t o o n ea n o t h e r , b u t a r e d i s t i n c t f r o m a m p h e t a m i n e , i n p os s e s s in g ab e n z y l i c o x y g e n f u n c t i o n .N o t a l l p h e n y l i s o p r o p y l a m i n e s ( e .g . , f e n f l u r a m i n e ) p o s s e s sa m p h e t a m i n e - l i k e c e n t r a l s t i m u l a n t c h a r a c t e r ( 6) ; h o w e v e r ,w e p r e v i o u s l y r e p o r t e d t h a t a l l f o u r a g e n t s p r o d u c e a m p h e t -a m i n e - l i k e e f f e ct s . A d d i t i o n a l b a c k g r o u n d i n f o r m a t i o n o na m i n o r e x ( 1 1 ), 4 - m e t h y l a m i n o r e x ( " U 4 E u h " ; 4 - M A X ) ( 7 ) , a n dc a t h i n o n e ( 5 , 6 ,8 ) m a y b e f o u n d i n t h e s e e a r l i e r r e p o r t s . 2 -

M e t h y l a m i n o - l - p h e n y l p r o p a n - l - o n e w a s o r i g i n a l ly s y n t he -s i zed in 1 9 36 (4 ) ; w e r e sy n th e s i zed th i s ag en t s ev e ra l y ea r s ag ot o c o m p l e t e a s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p ( S A R ) in v e s t i g a -t i o n a n d v e r i f y , o n t h e b a s i s o f o u r S A R s t u d i e s , t h a t i t w o u l da c t a s a c e n t r a l s t i m u l a n t O.e., s t r u c t u r a l l y , t h i s a g e n t i s t oc a t h i n o n e w h a t m e t h a m p h e t a m i n e i s t o a m p h e t a m i n e ) ( 9 ) .D u e t o i t s a c t i o n s a n d g r e a t e r p o t e n c y i n v a r i o u s p h a r m a -c o l o g i c a l a s s a y s r e l a t i v e t o c a t h i n o n e , w e c o i n e d t h e t e r mm e t h c a t h i n o n e ( 9) . T h is a g e n t h a s n o w a p p e a r e d o n t h e c l a n-d e s t i n e m a r k e t a s " C A T " ( 1 ) . I n t e r e s t i n g l y , i t h a s r e c e n t l yc o m e t o l i g h t t h a t m e t h c a t h i n o ne , u n d e r t h e n a m e o f e p -h e d r o n e ( " J E F F " ) , h a s s e e n w i d e s p r e a d a b u s e i n t h e f o r m e rS o v i e t U n i o n b u t t h a t r e p o r t s o f i t s a b u s e h a d b e e n s u p p r e s s e d[ ( 2 ) a n d J . T o l l i v e r , p e r s o n a l c o m m u n i c a t i o n ] . M e t h c a t h i -n o n e h a s n o w b e e n t e m p o r a r i l y s c h e du l e d u n d e r t h e e m e r -g e n c y s c h e d u l i n g p r o v i s i o n s o f t h e C o n t r o l l e d S u b s t a n c e sA c t ( 2 ).I n t h e p r e s e n t s t u d y , w e c o m p a r e t h e a b i l i t y o f m e t h c a t h i-n o n e a n d c ~ ( + ) 4 - m e t h y l a m i n o r e x t o p r o d u c e c o c a i n e - l i k es t i m u l u s ef f e c ts r e l a t iv e to t h e i r p a r e n t c o m p o u n d s : ( + ) c a t h i -n o n e a n d ( : i : ) a m i n o r e x .

To w hom requests fo r rep r in ts shou ld be addressed .229


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2 30 Y O U N G A N D G L E N N O NT A B L E 1

RESULTS OF STIMULUS GENERALIZATIONSTUDIES WITHCOCAINE-TRAINED AN IMALS

AgentCocaine-AppropriateD o s e R e s p o n d i n g ?

( m g / k g ) n * ( % )Coc aine HC1 1.0 6/6 10 (3)

2 . 0 6 /6 38 ( l l )4 .0 6/6 72 (9)6 .0 6/6 85 (9)8.O 6/6 97 (3)EDs0 = 2,60 (1.43-4.55) mg/kgSal ine (1 ml /k g) 6 /6 7 (2)( + )Cathinone 0 .1 5/5 0

0.25 5/5 4 (1)0.75 5/5 53 (17)1.5 5/5 93 (7)EDso = 0.69 (0.34-1.39) mg/kg(+)M ethca thinon e 0 .25 5/5 19 (4)0.50 5/5 58 (14)0.75 5/5 97 (1)EDso = 0.39 (0.23-0.67) mg/kg(+ )A m ino rex 0 .10 5 /5 25 (4)

0.25 5/5 43 (18)0.50 5/5 75 (17)0.75 5 / 5 9 6 ( 2)EDso = 0.22 (0.12-0.43) mg /kgc/s( + )4-MAX 0.5 5/5 8 (3)

1.0 5/5 33 (9)1.5 5/5 72 (14)2.0 5/5 90 ( 4 )E D ~ o = 1 . 1 1 ( 0 . 7 0 - 1 . 7 6 ) m g / k g

"elquniber ra ts o f respo nding/nu mbe r t rea ted.tD at a collected durin g 2.5-rain extinction session.

R e s p o n s e R a t e ?(responses/min)

14.2 (1.7)13.9 (2.0)15.1 (1.9)14.1 (1.7)14.8 (1.7)13.1 (1.8)1 5 . 2 ( 1 . 6 )13.9 (1.9)14.9 ( 2 . 1 )9 . 2 ( 2 . 1 )

13.7 (1.6)14.2 (1.9)14.9 (1.7)13.8 ( 1 . 6 )14.5 (1.7)1 5 . 2 (1.3)13.7 (2.1)13.5 (1.7)13.3 (2.1)12.6 (1.9)1 1 . 3 ( 1 . 2 )

METHODS u b j e c t s w e r e 6 m a l e S p r a g u e - D a w l e y r a t s w e i g h i n g 2 5 0 -3 0 0 g a t t h e s t a r t o f t h e s t u d 3 , . A n i m a l s w e r e f i r s t t r a i n e d t ol e v e r- p r e ss f o r s w e e t e n e d m i l k r e w a r d u s i n g s t a n d a r d t w o -l e ve r o p e ra n t c h a m b e r s ( C o u l b o u r n I n s t ru m e n t s M o d e l E l 0 -1 0) h o u s e d w i t h i n s o u n d - a n d l i g h t - a t t e n u a t i n g o u t e r c h a m -b e r s . O n c e l e v e r -p r e s s in g b e h a v i o r w a s a c q u i r e d , a n i m a l s w e r et r a i n e d t o d i s c r i m i n a t e I P i n j e c t i o n s o f c o c a i n e ( 8 . 0 m g / k g )f r o m 0 .9 07 o s t e r i l e s a l i n e ( l . 0 m l / k g ) , t h a t i s , r a t s w e r e t r a i n e d

t o r e s p o n d o n a v a r i a b l e - i n t e r v a l 15 - s ( V I 1 5 ) s c h e d u l e o f r e i n -f o r c e m e n t ; o n c e r a t e s o f r e s p o n d i n g s t a b i l i z e d , a n i m a l s r e -c e i v e d a n i n j e c t i o n o f d r u g o r s a l i n e 1 5 m i n p r i o r t o e a c hs e s si o n . D r u g o r s a l in e w a s a d m i n i s t e r e d o n a d o u b l e -a l t e r n a t i o n s c h e d u l e ( i . e. , 2 d a y s d r u g , 2 d a y s s a l i n e ) a n d t r a i n -i n g s e ss i o ns w e r e o f 1 5 m i n d u r a t i o n . O n e v e r y f if t h d a y ,l e a r n i n g w a s a s s e ss e d d u r i n g a n i n i t ia l 2 .5 - m i n n o n r e i n f o r c e d( e x t i n c t i o n ) p e r i o d f o l l o w e d b y a 1 2 . 5 - r a i n t r a i n i n g s e s s io n .D a t a c o l l e c t e d d u r i n g t h e e x t i n c t i o n p e r i o d i n c l u d e d p e r c e n td r u g - a p p r o p r i a t e le v e r re s p o n d i n g ( i .e . , t h e n u m b e r o f r e -s p o n s e s o n t h e d r u g d e s i g n a t e d le v e r + t o t a l n u m b e r o f r e -s p o n s e s , e x p r e s s e d a s a p e r c e n t ) a n d t o t a l r e s p o n s e s m a d ed u r i n g t h e 2 . 5 - r a in s e s s io n ( e x p r e s s e d a s r e s p o n s e s / r a i n ) .O n c e r a t s c o n s i s t e n t l y ( i .e . , f o r 3 c o n s e c u t iv e w e e k s ) m a d e> 8 0 % o f t h e i r r e sp o n s e s o n t h e d r u g - a p p r o p r i a t e l ev e r a f t e ra d m i n i s t r a t i o n o f d r u g a n d < 2007o o f t h e i r r e s p o n s e s o n t h e

s a m e l e v e r a f t e r i n j e c t i o n o f s a l i n e , s t i m u l u s g e n e r a l i z a t i o ns t u d i e s w e r e b e g u n . D u r i n g t h e s e i n v e s t i g a t i o n s , t e s t s e s s i o n sw e r e i n t e r p o s e d a m o n g t h e t r a i n i n g s e s s i o n s ; h o w e v e r , a f t e rt h e 2 . 5 - m i n e x t i n c t i o n p e r i o d a n i m a l s w e r e r e tu r n e d t o t h e i rh o m e c a g e s . D u r i n g g e n e r a l i z a t io n t e st s , r a t s w e r e i n j e c t e dw i t h d o s e s o f a t e s t c o m p o u n d a n d , 1 5 r a in l a t e r , te s t e d u n d e re x t i n c t i o n c o n d i t i o n s . S t i m u l u s g e n e r a l i z a t i o n w a s s a i d t oh a v e o c c u r r e d w h e n a n i m a l s m a d e > 8007 0 o f t h e i r r e s p o n s e so n t h e d r u g - a p p r o p r i a t e l e ve r . W h e r e s t i m u l u s g e n e r a l iz a t i o no c c u r r e d , E D s 0 v a l u e s ( i . e . , d o s e s a t w h i c h a n i m a l s w o u l d b ee x p e c t e d t o m a k e 5 0 7o o f t h e i r r e s p o n s e s o n t h e c o c a i n e -a p p r o p r i a t e l e v e r) w e r e c a lc u l a t e d b y t h e m e t h o d o f F i n n e y(3) .Drugs

R a c e m i c c a t h i n o n e H C I w a s a g i f t f r o m t h e W o r l d H e a l t hO r g a n i z a t i o n a n d c / s ( + ) 4 - m e t h y l a m i n o r e x H C I w a s a g i f tf r o m t h e D r u g E n f o r c e m e n t A d m i n i s t r at i o n . M e t h c a th i n o n eH C I w a s s y n t h e s iz e d in o u r l a b o r a t o r i e s ( 9) a n d ( + ) a m i n o r e xf u m a r a t e w a s a g if t f r o m M c N e i l L a b s ( F o r t W a s h i n g t o n ,P A ) . C o c a i n e H C 1 w a s p u r c h a s e d f r o m S i g m a C h e m i c a l C o .( S t . L o u i s , M O ) . A l l s o l u t io n s w e r e p r e p a r e d f r e s h d a i l y a n da l l a g e n t s w e r e a d m i n i s t e r e d v i a I P i n j e c t i o n i n a 1 . 0 - m l / k gi n j e c t i o n v o l u m e .


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NEW DESIGNER DRUGS 231RESULTS AND DISCUSSION

Cocaine has been employed in n umerous drug discrimina-tion studies and ma ny central stimulants, including cathinone,substitute for the cocai ne stimulus [reviewed in: (10)]. In thepresent investigation, rats were trained to discriminate 8 mg/kg (EDso = 2.6 mg/kg ; 7.6 #M/k g) coc aine from saline vehi-cle. Saline produced 70/o drug-appropriate responding (Table1). The cocaine stimulus generalized both to methcathinoneand 4-met hylamin orex in a dose-related fashion. Responserates for all doses of test compounds were comparable to thatfor cocaine (or saline) control rates.Methc athin one (ED~o = 0.39 mg/ kg; 1.9 /zM/kg) wasfoun d to be nearly twice as poten t as cathino ne (EDso = 0.69mg/kg; 3.7 gM/kg ); 4-methylaminorex (4-MAX; EDs0 =1.11 mg/kg; 5.2/~M/kg) is about six times less potent thanaminore x (EDs0 = 0.22 mg/kg ; 0.8/~M/ kg) (Table 1). Never-

theless, all four agents seem to possess cocaine-like stimuluscharacter, with the order o f potency being: aminorex >( )methcathinone > () cat hin one > c/s( )4-methyl-aminorex > cocaine.Altho ugh phenyl isopropylami nes bearing a benzylic oxy-gen func tion are generally only weakly active when the oxygenfunc tion is a hydroxyl group (e.g., ephe drine, norpseudoep he-drine), phe nylisopropyl amines with a benzylic oxygen in theform of a ketone (e.g., cathinone) or as part of a ring system(e.g., aminore x) are substa ntially more pote nt (6). The presentresults support and extend the results of our earlier studiesand demonstrate that these benzylic oxygen-containing phen-ylisopropylamines can produce cocaine-like stimulus effectsin animals.ACKNOWLEDGEMENTS

This work was supported in part by US PHS Grant DA 01642.

REFERENCES1. Bonner, R. C. Schedules of controlled substances. Temporaryplacement of methcathinone into Schedule I. Fed. Reg. 57:9080-9081; 1992.2. Bonner, R. C. Schedules of controlled substances. Temporaryplacement of methcathinone into Schedule I. Fed. Reg. 57:18824-18825; 1992.3. Finney, D. Probit analysis. London, UK: Cambridge UniversityPress; 1952.4. German Patent 634,002, August 14, 1936 (Chem. Abstr. 31:1921;1937).5. Glennon, R. A. Discriminative stimulus properties of phenyli-sopropylamine derivatives. Drug Alcohol Depend. 17:119-134;1986.6. Glennon, R. A. Psychoactive phenylisopropylamines, In: Melt-zer, H., ed. Psychopharmacology, third generation of progress.

New York: Raven Press; 1987:1627-1634.

7. Glennon, R. A.; Misenheimer, B. Stimulus properties of a newdesigner drug: 4-Methylaminorex ("U4Euh"). Pharmacol. Bio-chem. Behav. 35:517-521; 1989.8. Glennon, R. A.; Showalter, D. The effect of cathinone and sev-eral related derivatives on locomotor activity. Res. Comm. Subst.Abuse 2:186-192; 1981.9. Glennon, R. A.; Yousif, M.; Naiman, N.; Kalix, P. Methcathi-none: A new and potent amphetamine-like agent. Pharmacol.Biochem. Behav. 26:547-551; 1987.10. Woolverton, W. L. Discriminative stimulus effects of cocaine,In: Glennon, R. A.; Jarhe, T. U. C.; Frankenheim, J., eds. Drugdiscrimination: Applications in drug abuse research. Washington,DC: U.S. Government Printing Office; 1991:60-74.11. Young, R. Aminorex produces stimulus effects similar to amphet-amine and unlike those of fenfluramine. Pharmacol. Biochem.Behav. 42:175-178; 1992.

richard young and richard a. glennon- cocaine-stimulus generalization to two new designer drugs:...

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