WO1997030977A1

WO1997030977A1 - Selective d1 dopamine receptor agonists and partial agonists/antagonists

Info

Publication number: WO1997030977A1
Application number: PCT/US1997/002620
Authority: WO
Inventors: Mark Froimowitz; Emile Melvin Bellott; Robert Stevenson
Original assignee: Pharm-Eco Laboratories, Incorporated
Priority date: 1996-02-23
Filing date: 1997-02-19
Publication date: 1997-08-28
Also published as: JP2000506832A; AU2131697A; CA2247468A1; EP0883609A1

Abstract

Disclosed are compounds (1) and (2), and derivatives and analogs thereof, which are agonists for the D1 dopamine receptor. These compounds can be used to treat an individual with Parkinson's disease. Also disclosed are monohydroxy analogs of compounds (1) and (2), and derivatives and analogs thereof, which are partial D1 agonists or antagonists. These compounds can be used to treat an individual who abuses cocaine.

Description

SF.T.F.CTIVE Dl DOPAMINE RECEPTOR AGONISTS AND

PARTIAL AGONISTS/ANTAGONISTS

Background Parkinson's disease is characterized by the progressive death of presynaptic dopamine neurons in the substantia niσra that innervate postsynaptic striatal neurons and a resultant loss of striatal dopamine (Cedarbaum and Schleifer, "Drugs for Parkinson's disease, spasticity and acute muscle spasms", in Goodman and

Gilman's The Pharmacological Basis of Therapeutics, A.G. Goodman, T.W. Rail, A.S. Nies and P. Taylor, eds. Eighth Edition, McGraw Hill, pp. 463-484 (1992)) . The primary therapy for Parkinson's disease involves compensating for the loss of dopamine in the striatum. The most commonly administered drug for the treatment of Parkinson's disease is levodopa, which is converted into dopamine in the central nervous system. However, levodopa can cause severe side effects such as nausea, vomiting, cardiac arrhythmias and hypotension. Long-term use of levodopa can result in abnormal involuntary movements and psychosis. Consequently, there is a need for new treatments for Parkinson's disease.

Dopaminergic receptors have also been implicated in cocaine abuse. Specifically, cocaine is thought to block the reuptake of dopamine into dopamine-releasing neurons; as a consequence, dopamine levels can return to normal in the chronic presence of cocaine and be depleted in its absence. Subsequent reduced levels of synaptic dopamine are thought to cause the craving for cocaine that is associated with its abuse (Dackis and Gold, J. Substance

Abuse Treatmen t 2 : 139 (1985) and Kleber and Gawin, Am. J.

Drug Al cohol Abuse 12 : 235 (1986)) . Agonists for the Dl dopamine receptor subtype have been shown to be effective in treating Parkinson's disease induced in laboratory animals (Kebabian et al . , Eur. J.

Pharm . 229 : 203 (1992) , Taylor et al . , Eur . J. Pharm . 199 : 389 (1991) and Michaelides et al . , J. Med . Chem .

38:3445 (1995)) . Similarly, recent studies have shown that antagonists and partial agonists for the Dl dopamine receptor subtype may be effective in treating cocaine abuse (Caine and Koob, J. Pharm Exp . Ther . 270 : 209 (1994) and Bergman and Rosenzweig-Lipson, Problems of Drug Dependence,

1991 NIDA Research Monograph 119, page 185 (1992)) .

Therefore, there is a need for new compounds in new structural classes having selective activities for the Dl dopamine receptor.

Summary of the Invention

It has now been found that Compounds 1 and 2 have the necessary phar acophores in the regions of three dimensional space required for selective binding to the Dl dopamine receptor (Example 1) . Thus, it is expected that these compounds will be selective Dl receptor agonists and their monohydroxy analogs will be partial Dl receptor agonist .

(1) (2)

In one embodiment, the present invention is a compound represented by Structural Formula I :

R¹ is selected from the group consisting of -OH and -OR', wherein R⁴ is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group.

R² is selected from the group consisting of -H, -OH, -OR⁼ and a halogen, wherein R^D is selected from the group consisting of a lower alkyl group, a phenol protecting group and R⁴, when R⁴ is an alkylene group. R³ is selected from the group consisting of -H, an amine protecting group, a lower alkyl group and a lower alkyl group substituted with an aryl group. In one aspect, R³ is selected from the group consisting -H and a lower alkyl group.

In another embodiment, the compound of the present invention is represented by Structural Formula II:

wherein R -R" are as defined above for Structural Formula I . In another embodiment, the compound of the present invention is represented by Structural Formula III:

R³ ( in : wherein R"-R" are as defined above by Structural Formula I

In another embodiment, the compound of the present invention is represented by Structural Formula IV:

wherein R'-R³ are as defined above for Structural Formula I.

Yet another embodiment of the present invention is a method of stimulating a Dl dopamine receptor in an individual . The method comprises administering to the individual a stimulatory amount of a compound represented by Structural Formulas I, II, III or IV.

Compounds 1 and 2 can be used to treat individuals with Parkinson's disease. The monohydroxy analogs of 1 and

2 can be used to treat individuals who abuse cocaine. In addition, these compounds are useful for molecular modeling in order to further define the required spatial orientation of the amine and hydroxy-substituted phenyl ring for binding to the Dl receptor. They can also be used as standards in in vi tro binding assays for screening compounds for their ability to bind to the Dl receptor and for characterizing the effect of these kinds of compounds in the body. Descrip ion of the Ficnirpg

Figures IA and IB represent the stereoscopic images of the superposition of the hydroxylated phenyl rings of the energy minimized compounds 1 and 2 (light lines) onto the energy minimized structure of the Dl-selective full agonist dihydrexidine (dark lines) .

De ailed Description of the Invention

The features and other details of the invention will now be more particularly described with reference to the accompanying examples and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention.

"Stimulating" a Dl dopamine receptor (referred to herein as a "Dl receptor") refers to causing a molecule to bind, complex or interact with the Dl receptor so that the cellular activity which is affected or controlled by the Dl receptor either increases or decreases. For example, Dl agonists and antagonists, respectively, stimulate and inhibit the enzyme adenylate cyclase, which produces the cellular messenger cyclic adenosine monophosphate (AMP) (Clement-Cormrer et al . , Proc . Na tl . Acad . Sci . USA 71:1113 (1974) and Stoof and Kebabian, Nature 294:366 (1981)) . A compound which stimulates a Dl receptor can be an agonist, (i.e., a compound which causes the cellular activity affected or controlled by the Dl receptor to increase) or an antagonist (i.e., a compound which causes the cellular activity affected or controlled by the Dl receptor to decrease) . A compound which stimulates a Dl receptor can also be a partial agonist (a mixed agonist/antagonist, i.e., a compound which can act as either an agonist or an antagonist, depending on the tissue type) .

A "stimulatory amount" of a compound, as used herein, is the quantity of a compound which, when administered to an individual, results in a discernable increase or decrease of cellular activity affected or controlled by the Dl receptor. Administration of a stimulatory amount of a compound typically causes an observable physiological response resulting from the increase or decrease in a cellular activity under the control of a Dl receptor (see, for example, Taylor et al . , Eur. J. Pharm . 199 : 389 (1991) and Kebabian et al . , Eur. J. Pharm . 229 : 203 (1995)) . For example, Dl agonists can stimulate a bovine parathyroid gland to produce an increase in the release of parathyroid hormone (Brown et al . , Proc . Na tl . Acad . Sci . USA 74:4210

(1977) and Brown et al . , Mol . Pharm . 18 : 335 (1980)) . A

"stimulatory amount" can also refer to the amount of compound which decreases or alleviates the symptoms of a disease involving the Dl receptor or a disease involving molecules, such as dopamine, which stimulate the Dl receptor, e.g. Parkinson's disease or cocaine abuse. Typically, a "stimulatory amount" of the compound ranges from about 1 mg/day to about 1000 mg/day.

Compounds of the invention which act as Dl receptor agonists can be used in a method of treating an individual afflicted with Parkinson's disease. The method comprises administering a therapeutically effective amount of the Dl receptor agonist to the individual afflicted with Parkinson's disease. Compounds of the invention which are Dl receptor agonists are compounds represented by Structural Formulas I-IV, wherein R^: is selected from the group consisting of -OH and -OR^", and wherein R^: is as defined above. Examples of compounds which can be used for the treatment of Parkinson's disease include compounds represented by Structural Formulas II and IV, wherein R¹ and R² are each -OH and R³ is -H. Other examples include compounds represented by Structural Formulas I and III, where R^" and R^: are each -OH and R³ is -H or -CH₃.

Compounds of the invention which act as Dl receptor partial agonist can be used in a method for treating an individual who abuses cocaine. In this embodiment, the method of the invention comprises administering a therapeutically effective amount of the Dl receptor partial agonist to an individual who abuses cocaine.

Compounds of the invention which act as a Dl receptor partial agonist are compounds represented by Structural Formulas I-IV, wherein R^~ is -H or a halogen. Examples of compounds which can be used for the treatment of cocaine abuse include compounds represented by Structural Formulas II and IV, wherein R¹ is -OH and R and R" are each -H. Other examples include compounds represented by Structural Formulas I and III, wherein R¹ is -OH, R^: is -H and R-^' is -H or -CH₃.

A "therapeutically effective" amount of a compound is the amount of compound which decreases or alleviates the severity of the symptoms associated with a disease, e.g., Parkinson's disease or cocaine abuse, in an individual being treated with the compound. In the case of treatment of cocaine abuse, a "therapeutically effective" amount of a compound can be the amount of compound which decreases an addicted individual's craving for cocaine. Typically, a "therapeutically effective amount" of the compound ranges from about 1 mg/day to about 1000 mg/day.

As used herein, a "lower alkyl" group is a substituted or unsubstituted C1-C12 alkyl group, and can be straight- chained, branched or cyclic. A lower alkyl group can also include one or more units of unsaturation. As used herein, an "aryl group" includes, for example, phenyl, substituted phenyl, heteroaryl (e.g. thienyl, furanyl, pyridinyl and benzothienyl) or substituted heteroaryl groups. Examples of suitable substituents on an aryl or heteroaryl group include -CN, -N0_:, halogen, lower alkyl, -OR, -NHR, and -SR, wherein R is a C1-C6 alkyl group or a protecting group for an alcohol, amine or thiol group. Examples of suitable halogens include chlorine, bromine and fluorine. Alkylene groups can be used to form a bridge between two ort o phenolic oxygens, e.g., R' and R³ in Structures

I-IV, taken together, can form an alkylene group.

Examples of suitable "alkylene groups" include

-(CHO-, -(CH_;-CH_:)-, -(CHX)-, -(CXY)-, - (CHX-CH - and -(CHX-CHY)-, wherein X and Y are C1-C4 alkyl groups and are independently chosen. A preferred alkylene group is methylene.

"Protecting group" has the definition commonly afforded to the term, namely a chemical moiety bonded to a functional group in a molecule, which is removable when exposed to suitable chemical reagent (s) or enzyme (s) to regenerate a free functional group.

Examples of suitable phenol and alcohol protecting groups include t-butyl, methoxymethyl, 2-tetrahydropyranyl, O O

II II

2 -tetrahydrof ranyl , -CO dower alkyl ) , ( lower alkyl ) -0- C- ,

O O

II II (lower alkyl) -NH-C- , -CO(aryl) , silyl esters, (e.g. triisopropylsilyl and t-butyldimethyl silyl) , trifluoracetate, 2-methoxyethoxy-methyl, siloxymethyl, benzyloxycarbonyl (BOC) and carboxycarbonyl (CBZ) . Suitable amine protecting groups include t-butyloxycarbonyl (BOC) , benzyloxycarbonyl (CBZ) , 9-fluorenylmethoxycarbonyl (f-MOC) , 2, 2, 2-trichloroethoxycarbonyl, 2-haloethoxy- carbonyl, benzoyl, phthalimidyl, diphenylphosphinyl and benzensulfonyl . Other suitable phenol, alcohol, amine and thiol protecting groups are given in Greene, "Protecting Groups in Organic Synthesis," John Wiley and Sons, Second Edition, (1991) , and are within the scope of the present invention.

The compounds of the present invention can be administered to an individual in the form of a pro-drug, i.e., the compound being administered is converted into the active agent in vivo . A pro-drug is often used to enhance certain desirable properties of the compound. For example, the pro-drug can have greater lipophilicity than the parent drug and, therefore, greater ability to cross the blood brain barrier. A pro-drug can also stabilize the pharmacologically active substance, e.g., by preventing metabolism of the pharmacologically active substance by, for example, oxidation.

The compounds of the present invention can be converted into pro-drugs by protecting the phenol (s) and/or amine functionalities with groups that are capable of being removed in vivo . For example, phenolic esters, carbonates and carbamates are degraded by cellular enzymes to yield phenols (Dittert et al . , J. Pharm. Sci . 57 : 783 (1968) , Dittert et al . , J. Pharm . Sci . 57:828 (1968) , Dittert et al . , J. Pharm . Sci . 58 : 551 (1969) and Ratie et al . , J.

Pharm . Sci . 59 : 1139 (1970)) . Suitable, phenol protecting groups which can be removed in vivo to regenerate the

0 il free phenol, include (C1-C8 alkyl) -CO-, (C1-C8 alkyl) -

0 0

1 il

O-C- and (C1-C8 alkyl) -NH-C- . Also included is when the phenols are protected in the form a methylene dioxy group. In addition, a variety of carbamate groups used to protect amines are known to undergo spontaneous cleavage in solution at kinetically favorable rates (Saari, et al . J.

Med . Chem . , 33 : 91 (1990)) and would thus be expected to degrade in vivo . Carbamates are also degraded enzymatically, (King, et al . , Biochemis try, 26 : 2294

(1987)) , particularly in blood (Tunek, et al . , Biochemi cal

Pharmacology, 37:3867 (1988)) to afford an unprotected amine. Suitable amine protecting groups which are

O

Ii removable in vivo include phenyl-O-C- and (C1-C6

0

II alkyl substituted phenyl) -0-C- and (C1-C3 alkoxy 0

II substituted phenyl) -O-C- .

The compounds of the present invention can be administered by a variety of known methods, including orally, rectally, or by parenteral routes (e.g. , intramuscular, intravenous, subcutaneous, nasal or topical) . The form in which the compounds are administered will be determined by the route of administration. Such forms include, but are not limited to capsular and tablet formulations (for oral and rectal administration) , liquid formulations (for oral, intravenous, intramuscular or subcutaneous administration) and slow releasing microcarriers (for rectal, intramuscular or intravenous administration) . The formulations can also contain a physiologically acceptable vehicle and optional adjuvants, flavorings, colorants and preservatives. Suitable physiologically acceptable vehicles may include saline, sterile water, Ringer's solution, and isotonic sodium chloride solutions. The specific dosage level of active ingredient will depend upon a number of factors, including, for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual being treated.

The compounds of the present invention used in the treatment of an individual with Parkinson's disease can be co-administered with other pharmaceutically active agents used in the treatment of Parkinson's disease. The compounds of the present invention used in the treatment of an individual who abuses cocaine can be combined with other therapies used to treat individuals who abuse cocaine.

Such therapies can include the co-administration of other pharmaceutically active agents used to treat cocaine abuse or psychological therapies.

When the compounds of the present invention are used in combination with other pharmaceutically active agents, the specific combination will vary, depending on a number of factors, including, for example, activity of the agents, their side-effects, and the weight, age, sex and general health of the individual being treated. The preparation of compounds of the present invention are shown in Schemes 1 and 2 and described more fully in Examples 2 and 3.

The invention is further illustrated by the following examples, which are not intended to be limiting in any way.

Example 1 - Energy Minimization Studies on Compounds 1 and 2

Energy minimization studies were performed on Compounds 1 and 2. The energy minimized structures of 1 and 2 have been superimposed onto the energy minimized conformation of the active enantiomer of dihydrexidine (Knoerzer et al . , J.

Med . Chem . 37:2453 (1994)), as shown in Figures IA and IB.

Dihydrexidine is a known Dl selective agonist.

Compounds 1 and 2 present similar nonplanar pharmacophores with the amine group and phenyl rings placed in similar regions of three dimensional space, as in dihydrexidine and other Dl selective compounds (Froimowitz and Bellott, J. Mol . Model . 1:36 (1995)) .

Calculations of the conformational flexibilities of 1 and 2 were performed and compared with that of dihydrexidine. These studies show that in dihydrexidine, one phenyl ring can be either above or below the plane of the other, due to close contacts between the phenyl rings (Fromowitz and Bellott, J. Mol . Model . 1 : 36 (1995)) . Both conformers were energy minimized with the result that the conformer shown in Figures IA and IB is preferred by 1.5 kcal/mole. This is also the conformer observed in the crystal state of a dihydrexidine analog (Knoerzer et al .

1994) . These results also indicate that Compounds 1 and 2 have two possible conformations of the two-carbon link between the phenyl rings and that there is a substantial energy difference (3.4 kcal/mole for 2) between these two conformers. Compound 1, as with other nonplanar tricyclic structures, has additional flexibility in that the tricyclic structure can invert (Froimowitz and Ramsby, J^".

Med . Chem . 34 : 1101 (1991)) and the preferred folding will be the one in which the side chain is pseudoequatorial . In addition, the amine-containing side chain can be conformationally trans to either phenyl ring and there is little energy difference between these possibilities due to the near symmetry of the molecule. Compound 2 is a less flexible analog of 1 and the ammonium hydrogens are similarly placed to those in dihydrexidine.

The monohydroxy analog of the Dl receptor agonist dihydrexidine is a partial Dl agonist (Seiler et al . , J. Med . Chem. 36 : 911 (1993)) . In addition, the same modification to the catechol-containing partial agonist apomorphine produces a Dl antagonist (Schaus et al J. Med.

Chem. 33 : 600 (1990) . Thus, it is expected that the monohydroxy analog of 1 and 2 will result in a Dl partial agonist or antagonist.

Energy minimization of the compounds in this study were performed with respect to all internal coordinates using the MM2-87 program and parameter set of Allinger and Yuh, Quantum Chem . Program Exch . 12.-program 395 (1980) . All calculations were performed for the protonated molecule. Initial Cartesian coordinates of the molecules were generated with PCMODEL program (Serena Software, Box 3076, Bloomington, IN 47402-3076) or the DRIVER option of the MM2-87 program. The dielectric constant was set to 80 and the hydrogen bonding terms involving the ammonium group were set to zero to approximate a water solution and to prevent intramolecular electrostatic forces from dominating the calculations in the absence of explicit water molecules (Froimowitz, J^". Comput. Chem. 14:934 (1993) and Froimowitz et al . , J. Med . Chem . 36 :2219 (1993)) . To ensure complete convergence of the calculations, the convergence criteria was set to 1/8 of its default.

Example 2 - Synthesis of Compound 1

The preparation of the dimethoxybenzalphthalide 8 is carried out by reaction of 2, 3-dimethoxyphenylacetic acid 4 with phthalic anhydride 6 in the presence of sodium acetate (Weiss, Organic synthesis, Collective Volume II, page 61) . Catalytic reduction (Raney nickel/hydrogen) of the dimethoxybenzalphthalide 8 yields the phenethylbenzoic acid

10. Cyclization of the phenethylbenzoic acid 10 with polyphosphoric acid yields the cycloheptadienone 12

(Winthrop et al . , J. Org . Chem . 27:230 (1962)) .

Condensation of the cycloheptadienone 12 with nitromethane yields the nitroalkane 14, which is catalytically hydrogenated to produce compound 16. Chiral resolution of the racemate is carried out by HPLC with a chiral column such as CHIRACEL OD (J.T. Baker) (Froimowitz et al . , Drug Design and Discovery 13 : 13 (1995)) .

Demethylation of each enantiomer with BBr₃ or HBr provides the final optically pure product 1. Alkyl groups are introduced onto the amine by reductive alkylation (Gribble et al . , J. Am . Chem. Soc ,

96 : 1812 (1974) ) .

Example 3- Synthesis of Compound 2

To prevent cyclization to the activated benzo ring, the aryl hydrogens of the activated benzo ring of the cycloheptadienone 12 are protected by electrophilic dibromination with Br to give the cycloheptadienone 18.

The carbonyl group of the cycloheptadienone 18 is converted to a methylamino group by successive reduction with NaBH, , alcohol tosylation, displacement with cyanide and reduction to produce compound 20. The benzocyclo-heptatriene- isoquinoline ring system is then produced according to literature methods (Humber et al . , J. Heterocyclic Chem.

3:247 (1966)) to afford lactam 22. Reduction of lacta 22 with lithium aluminum hydride effects the reduction of the lactam functionality and the reductive debromination of the protecting halogens to produce compound 24. Chiral resolution is carried out as described in Example 1. Demethylation is then accomplished with BBr, or HBr to give 2.

Exam l 4 - Binding Assay for the Dl Receptor

The binding assay for the Dl receptor utilizes homogenized rat striatal membrane preparations. An IC₅ curve is generated from 10 concentrations of the test compound (10^"" to 10^_= M) performed in duplicate using the LIGAND program for data analysis (Munson and Rodbard, Anal.

Biochem . 107 : 220 (1980)) . Binding is assessed by filtering incubates on polyethylenimine-presoaked Whatman GF/B filters and by scintillation counting (Billard et al . , Life

Sci . 35:1885 (1984)) . The radioactive ligand is ^"H SCH-

23390 at a concentration of 0.3 nM and the buffer consists of 50 mM Tris-HCl (pH 7.4) , 120 mM KCl, 2 mM CaCl_: and 1 mM MgCl; (Billard et al . , Life Sci . 35:1885 (1984)) . Incubation time is fifteen minutes at 37°C. Non-specific binding is defined with 1 μM (+) -butacla ol .

Equivalents

Those skilled in the art will know, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These and all other equivalents are intended to be encompassed by the following claims .

Claims

GLAIMS

What is claimed is

1. A compound represented by the following structural formula:

wherein:

R¹ is selected from the group consisting of -OH and -OR", wherein R" is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R^: is selected from the group consisting of -H, -OH, -OR⁼ and a halogen, wherein R⁼ is selected from the group consisting of a lower alkyl group, a phenol protecting group and R", when R" is an alkylene group; and

R³ is selected from the group consisting of -H, an amine protecting group, a lower alkyl group and a lower alkyl group substituted with an aryl group.

The compound of Claim 1 wherein: a) R^" and R^: are each -OH; and b) R³ is -H or -CH, . 3. The compound of Claim 1 wherein: a) R¹ is -OH; b) R² is -H; and c) R³ is -H or -CH₃.

4. A compound represented by the following structural formula:

wherein:

R¹ is selected from the group consisting of -OH and -OR", wherein R⁴ is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R" is selected from the group consisting of -H, -OH, -OR⁵ and a halogen, wherein R is selected from the group consisting of a lower alkyl group, a phenol protecting group and ^1*, when R^" is an alkylene group;

R" is selected from the group consisting of -H, an amine protecting group, a lower alkyl group and a lower alkyl group substituted with an aryl group. The compound of Claim 4 wherein: a) R^" and R² are each -OH; and b) R³ is -H.

The compound of Claim 4 wherein: a) R^" is -OH; and b) R^" and R³ are each -H.

A method of treating an individual who abuses cocaine, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:

wherein:

R¹ is selected from the group consisting of -OH and -OR'', wherein R⁴ is selected from the group consisting of a lower alkyl group and a phenol protecting group;

R² is selected from the group consisting of -H and a halogen; and

R³ is selected from the group consisting of -H, an amine protecting group, a lower alkyl group and a lower alkyl group substituted with an aryl group. The method of Claim 7 wherein:

R¹ is -OH; and b) R² and R³ are each -H.

wherein:

R¹ is selected from the group consisting of ■OH and -OR⁴, wherein R" is selected from the group consisting of a lower alkyl group and a phenol protecting group;

R² is selected from the group consisting of -H and a halogen; and

10. The method of Claim 9 wherein a) R¹ is -OH; and b) R² and R^" are each -H. 11. A method of treating an individual with Parkinson's disease comprising administering to the individual a therapeutically effective amount of a compound represented by the following structural formula:

wherein:

R" is selected from the group consisting of -OH and -OR' , wherein R⁴ is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R² is selected from the group consisting of -OH and -0R^:, wherein R⁼ is selected from the group consisting of a lower alkyl group, a phenol protecting group and R⁴ , when R⁴ is an alkylene group;

12. The method of Claim 11 wherein: a) R^π and R² are each -OH; and b) R³ is -H. 13. A method of treating an individual with Parkinson's Disease comprising administering to the individual a therapeutically effective amount of a compound represented by the following structural formula:

wherein:

R^* is selected from the group consisting of -OH and -OR", wherein R" is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R^: is selected from the group consisting of -OH and -OR⁵, wherein R" is selected from the group consisting of a lower alkyl group, a phenol protecting group and R , when R⁴ is an alkylene group;

R" is selected from the group consisting of -H, an amine protecting group, a lower alkyl group and a lower alkyl group substituted with an aryl group.

14. The method of Claim 13 wherein: a) R" and R are each -OH; and b) R³ is -H or -CH,.

15. A method of stimulating a Dl dopamine receptor in an individual, comprising administering to the individual a stimulatory amount of a compound represented by the following structural formula:

wherein:

R¹ is selected from the group consisting of -OH and -OR⁴, wherein R⁴ is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R² is selected from the group consisting of -H, -OH, -0R⁼ and a halogen, wherein R³ is selected from the group consisting of a lower alkyl group, a phenol protecting group and R', when R" is an alkylene group; and

16. A method of stimulating a Dl dopamine receptor in an individual, comprising administering to the individual a stimulatory amount of a compound represented by the following structural formula:

wherein:

R^" is selected from the group consisting of -OH and -OR", wherein R⁴ is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R^" is selected from the group consisting of -H, -OH, -0R^: and a halogen, wherein R³ is selected from the group consisting of a lower alkyl group, a phenol protecting group and R when R" is an alkylene group; and

R^J is selected from the group consisting of -H, an amine protecting group, a lower alkyl group and a lower alkyl group substituted with an aryl group.

17. A compound represented by the following structural formula:

wherein:

R^l is selected from the group consisting of -OH and -OR⁴, wherein R⁴ is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R² is selected from the group consisting of -H, -OH, -OR⁵ and a halogen, wherein R^D is selected from the group consisting of a lower alkyl group, a phenol protecting group and R^~~ , when R' is an alkylene group; and

18. The compound of Claim 17 wherein: a) R¹ and R² are each -OH; and b) R³ is -H or -CH,.

19. The compound of Claim 17 wherein: a) R¹ is -OH; b) R² is -H; and c) R³ is -H or -CH, . 20. A compound represented by the following structural formul :

R~

wherein:

R¹ is selected from the group consisting of -OH and -OR⁴, wherein R" is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R² is selected from the group consisting of -H, -OH, -OR⁵ and a halogen, wherein R^: is selected from the group consisting of a lower alkyl group, a phenol protecting group and R" , when R" is an alkylene group; and

21. The compound of Claim 20 wherein: a) R" and R² are each -OH; and b) R³ is -H.

22. The compound of Claim 20 wherein: a) R¹ is -OH; and b) R² and R³ are each -H. 23. A method of treating an individual who abuses cocaine, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:

wherein:

R¹ is selected from the group consisting of -OH and -OR", wherein R⁴ is selected from the group consisting of a lower alkyl group and a phenol protecting group;

R² is selected from the group consisting of -H and a halogen; and

R- is selected from the group consisting of -H, an amine protecting group, a lower alkyl group and a lower alkyl group substituted with an aryl group.

24. The method of Claim 23 wherein: a) R" is -OH; and b) R^: and R³ are each -H.

25. A method of treating an individual who abuses cocaine, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:

wherein:

R^" is selected from the group consisting of -OH and -OR⁴, wherein R⁴ is selected from the group consisting of a lower alkyl group and a phenol protecting group;

R² is selected from the group consisting of -H and a halogen; and

26. The method of Claim 25 wherein: a) R¹ is -OH; b) R^: is -H; and c) R³ is -H or -CH,

27. A method of treating an individual with Parkinson's Disease comprising administering to the individual a therapeutically effective amount of a compound represented by the following structural formula:

wherein:

R- is selected from the group consisting of -OH and -OR⁴, wherein R⁴ is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R² is selected from the group consisting of -OH and -OR⁵, wherein R^D is selected from the group consisting of a lower alkyl group, a phenol protecting group and R⁴, when R⁴ is an alkylene group; and

28. The method of Claim 27 wherein: a) R^: and R² are each -OH; and b) R³ is -H.

29. A method of treating an individual with Parkinson's Disease comprising administering to the individual a therapeutically effective amount of a compound represented by the following structural formula:

wherein:

R is selected from the group consisting of -OH and -OR⁴, wherein R" is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R² is selected from the group consisting of -OH and -OR⁵, wherein R is selected from the group consisting of a lower alkyl group, a phenol protecting group and R⁴, when R^"1 is an alkylene group; and

30. The method of Claim 29 wherein: a) R" and R² are each -OH; and b) R³ is -H or -CH, .

31. A method of stimulating a Dl dopamine receptor in an individual, comprising administering to the individual a stimulatory amount of a compound represented by the following structural formula:

wherein:

R² is selected from the group consisting of -H, -OH, -OR⁵ and a halogen, wherein R⁵ is selected from the group consisting of a lower alkyl group, a phenol protecting group and R", when R" is an alkylene group; and

32. A method of stimulating a Dl dopamine receptor in an individual, comprising administering to the individual a stimulatory amount of a compound represented by the following structural formula:

R

wherein:

R^" is selected from the group consisting of -OH and -OR^", wherein R⁴ is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;

R^" is selected from the group consisting of -H, -OH, -OR³ and a halogen, wherein R⁵ is selected from the group consisting of a lower alkyl group, a phenol protecting group and R^", when R" is an alkylene group; and