Therapeutic compounds

1. A compound consisting of

a) a ligand moiety for a monoamine transporter or receptor selected from dopamine, norepinephrine, and serotonin transporters or receptors wherein the ligand has the following Formula 1:

in which:

the 2-, 3-, 6-, or 7-positions are α or β;

the compounds are racemic or 1 R-or 1 S-configured;

X =CHR 3 , CHR 1 , CHW 1 , CW 1 W 1 , NR 3 , NR 9 , NSO 2 R 3 , NSO 2 R 1 or CX 2 W, with the N or C atom being a member of the ring;

Ar =Phenyl or 1-naphthyl or 2-naphthyl, unsubstituted or substituted with one or more group selected from: —H; —Br; —Cl; —I; —F; —OH; —CH 3 ; —CF 3 ; —NO 2 ; —NH 2 ; —CN; —NHCOCH 3 , —C(CH 3 ) 3 , —C(CH 3 ) CH 3 , (CH 2 ) q CH 3 , where q=0-6; —COCH 3 ; alkyl; alkenyl; alkynyl; allyl; isopropyl; isobutyl; wherein each substituent can be at the 2, 3 and/or 4 position of the ring;

W or X 2 =H, OH, OCH 3 ,OAc, OCOR 4 , CH 3 , (CH 2 ) n CH 3 , R 4 ;

W 1 =H, Br, Cl, I, F, OH, OCH 3 , CF 3 , NO 2 , NH 2 , CN, NHOOCH 3 , N(CH 3 ) 2 , (CH 2 ) n CH 3 , COCH 3 , or C(CH 3 ) 3 ;

R 1 =H, COOCH 3 , COOR 4 ,COR 4 , CH 2 OH, (CH 2 ) n OH, (CH 2 ) n OR 4 , CR 3 =NOR 3 , CH═NR 3 ;

R 2 =H, OH,OCOR 4 ;

R 3 =H, CH 3 , CH 2 Ar, (CH 2 ) n Ar, Ar, lower alkyl, lower alkenyl or lower alkynyl; CH 2 CH═CHZ, (CH 2 ) n OH, (CH 2 ) n OR 4 , CH═CHZ; CH 2 J-Maleimide, CH 2 JN-Maleimide where J =CH 2 or O;(CH 2 ) n OCOCH 3 ; (CH 2 ) n OCOCH 2 OCH 3 ; (CH 2 ) n -morpholine; (CH 2 ) n -piperidine; (CH 2 ) n -piperazine;

R 4 =CH 3 , CH 2 CH 3 , alkyl, alkenyl, alkynyl, allyl, isopropyl, isobutyl;

R 9 =H, COOCH 3 , COOR 4 ,COR 4 , CH 2 OH, (CH 2 ) n OH, (OH 2 ) n OR 4 ;

n =0-4;

m =0-4;

Z =F, Cl, I or Br; and

b) a linker-acceptor moiety connected to the ligand, comprising

1) an acceptor moiety that covalently binds the transporter or receptor; and

2) a linker which attaches the ligand to the acceptor moiety, the linker comprising a —CH 2 — moiety attached to X; wherein the Linker is selected from—(CH 2 ) n O(CH 2 ) m —,—(CH 2 ) n OCO(CH 2 ) m —,—(CH 2 ) n COO(CH 2 ) m —, or—(CH 2 ) n S(CH 2 ) m —, wherein n =1-4 and m =0-4; and wherein the linker comprises a cleavable bond, cleavage of which produces at least two components, (1) a barb comprising the acceptor moiety and (2) the ligand, wherein the ligand is released from the compound.

2. The compound of claim 1 wherein the acceptor moiety is a radical acceptor.

3. The compound of claim 1 wherein the acceptor moiety is an epoxide.

4. The compound of claim 1 wherein the acceptor moiety is an alkenyl moiety.

5. The compound of claim 1 wherein the ligand is a tropane and the monoamine transporter is the dopamine transporter.

6. The compound of claim 1 wherein the ligand is a tropane moiety and the monoamine transporter is the serotonin transporter.

7. The compound of claim 1 wherein the acceptor moiety inhibits binding of cocaine at a monoamine transporter or receptor.

8. The compound of claim 1 wherein the compound inhibits binding of cocaine at a muscarinic cholinergic receptor.

9. The compound of claim 7 or 8 wherein the ligand has an Ic 50 of less than 500 nM with respect to [ 3 H]CFT inhibition of DAT.

10. The compound of claim 1 wherein the monoamine transporter is DAT.

11. The compound of claim 10 wherein binding of the acceptor moiety to the monoamine transporter allows DA transport.

12. The compound of claim 1 where the linker-acceptor moiety is selected from the following: (CH 2 ) n OCH 2 CH═CH 2 ; (CH 2 ) n D(CH 2 ) m CH═CH 2 ; (CH 2 ) n SCH 2 CH═CH 2 ; (CH 2 ) n OCH 2 (CH 2 ) n CH═CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH═CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH—(O : epoxide)-CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH 3 ; (CH 2 ) n OCO(CH 2 ) m OCH 3 ; (CH 2 ) n OCOCH(CH 3 ) 3 ; (CH 2 ) n OCO(CH 2 ) m CH(CH 3 ) 2 ; (CH 2 ) n OCO(CH 2 ) m CH 3 ; (CH 2 ) n OCOCH 2 CH(R 2 ) 2 ; (CH 2 ) n OCOCHR 4 CH(R 2 ) 2 ; (CH 2 ) n OCOCHCHR 2 ;( CH 2 ) n OCHCH(R 2 ) 2 ; (CH 2 ) n OCOCH 3 ; (CH 2 ) n OCOCH 2 OCH 3 ;

where D =O or S; J=CH 2 or O; n=0-4; m=0-4; and p=0-3.

13. The compound of claim 1 , wherein the Acceptor is selected from the following structures:

where A is —(CH 2 ) n -D-(CH 2 ) m —;

D =CH 2 , (CH 2 ) p ,O, S, NH, SO and SO 2 ;

R 5 is H, CH 3 ,(CH 3 ) 2 , (CH 2 ) n SO 3 Q, alkyl, (alkyl) 2 , alkenyl, alkynyl, Ar, F, Cl, OCH 3 and

Q=K + , Na + , Li + , Ca 2+ , NH 4 + , RNH 3 + , or other pharmaceutically acceptable salts.

14. The compound of claim 1 , wherein the Acceptor is selected from the following structures: —CH 2 CH═CH 2 ;

15. The compound of claim 1 wherein X is O.

16. The compound of claim 1 wherein R 2 is H.

17. The compound of claim 1 wherein Ar is phenyl substituted with substituents selected from: one or more —Cl, one or more —F, and a combination of —C1 and —F.

18. The compound according to claim 1 , wherein the linker-accertor comprises a moiety selected from the group consisting of: —(CH 2 ) n CH═CH 2; —CH 2 O(CH 2 ) n CH═CH 2 —CH 2 OCO(CH 2 ) n CH═CH 2;

where n =1-4.

19. A pharmaceutical composition comprising a compound according to claim 1 , together with a pharmaceutically acceptable carrier.

20. A method of inhibiting binding of cocaine to the DAT comprising administering an effective amount of a compound according to claim 1 , wherein the transport of dopamine is not completely inhibited.