Chemical & Pharmacological Studies of Cocaine Analogues

Kozikowski, Alan Paul

Abstract

The basic premise of this proposal is that the cocaine recognition site and the dopamine uptake site are not identical. If this notion is correct, and indeed we have acquired further data to support this possibility (Preliminary Studies) then it may well be possible to discover cocaine analogues which can bind to the cocaine recognition site but unlike cocaine, fail to inhibit or only weakly inhibit the reuptake of cocaine through the associated dopamine transporter. The discovery of such partial agonists or antagonists of cocaine may be valuable from a therapeutic standpoint, for such compounds: (1) may be used to counter some of the adverse side effects of cocaine in cases of cocaine overdose; or (2) may lead to the development of a """"""""cocaine antagonist"""""""" for use in maintaining patients in treatment programs. Other uses for functionally altered analogues of cocaine can also be envisioned including the possible application of such compounds to diseases like schizophrenia. To better get at the root of cocaine abuse and to develop more directed strategies for treatment, we believe it essential to continue our efforts to learn more about the basic chemistry and pharmacology of cocaine. Accordingly, we believe it most important to base our program on the discovery of the structural-functional relations that govern cocaine's pharmacology.
The specific aims of this combined chemical synthesis/pharmacology program are as follow: (1) to synthesize selected analogues of cocaine in order to obtain a more complete understanding of its structure activity relationships; particular emphasis will be placed on the further exploration of compounds found to exhibit a weak antagonistic action; (2) to pharmacologically characterize all newly synthesized compounds by studying their properties in mazindol binding studies and on dopamine synaptosomal uptake as well as release in slices; and (3) in cases where compounds of unusual activity are found, to examine the effects of the new analogues in paradigms in which the potential antagonism of cocaine's action on dopamine uptake and release could be realized. The information obtained from the specific aims delineated above will serve: (a) to provide further information as to the bound conformation of cocaine at its recognition site(s); (b) to reveal details of the topography of these sites; and (c) to identify structural features which may be relevant to the discovery of cocaine partial agonists and antagonists. Results of our efforts to date which include the discovery of a weak cocaine antagonist are detailed in the Preliminary Studies Section.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Drug Abuse (NIDA)
• Type: Research Project (R01)
• Project #: 5R01DA010458-02
• Application #: 2517997
• Study Section: Human Development Research Subcommittee (NIDA)
• Project Start: 1996-09-30
• Project End: 2000-07-31
• Budget Start: 1997-09-01
• Budget End: 1998-07-31
• Support Year: 2
• Fiscal Year: 1997

Institution

• Name: Georgetown University
• Department: Neurology
• Type: Schools of Medicine
• DUNS #: 049515844
• City: Washington
• State: DC
• Country: United States
• Zip Code: 20057

Publications

Musachio, John L; Hong, Jinsoo; Ichise, Masanori et al. (2006) Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors. Bioorg Med Chem Lett 16:3101-4

Iso, Yasuyoshi; Grajkowska, Ewa; Wroblewski, Jarda T et al. (2006) Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications. J Med Chem 49:1080-100

Kozikowski, Alan P; Zhao, Lianyun; Zhang, Ao et al. (2006) Structural remodeling of cocaine: design and synthesis of trisubstituted cyclopropanes as selective serotonin reuptake inhibitors. ChemMedChem 1:58-65

Wee, Sunmee; Wang, Zhixia; He, Rong et al. (2006) Role of the increased noradrenergic neurotransmission in drug self-administration. Drug Alcohol Depend 82:151-7

Ukairo, Okechukwu T; Bondi, Corry D; Newman, Amy Hauck et al. (2005) Recognition of benztropine by the dopamine transporter (DAT) differs from that of the classical dopamine uptake inhibitors cocaine, methylphenidate, and mazindol as a function of a DAT transmembrane 1 aspartic acid residue. J Pharmacol Exp Ther 314:575-83

Zhou, Jia; Klass, Thomas; Johnson, Kenneth M et al. (2005) Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants. Bioorg Med Chem Lett 15:2461-5

He, Rong; Kurome, Toru; Giberson, Kelly M et al. (2005) Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhi J Med Chem 48:7970-9

Petukhov, Pavel A; Zhang, Jianrong; Wang, Cheng Z et al. (2004) Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: evidence of unfavorable interactions proximal to the 3alpha-position of the piperidine ring. J Med Chem 47:3009-18

Zhou, Jia; He, Rong; Johnson, Kenneth M et al. (2004) Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization. J Med Chem 47:5821-4

Zhou, Jia; Zhang, Ao; Klass, Thomas et al. (2003) Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: synthesis and evaluation of their uptake inhibition at monoamine transporter sites. J Med Chem 46:1997-2007