Tags

Type your tag names separated by a space and hit enter

Structure-activity relationships at monoamine transporters for a series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation.
J Med Chem. 2004 Jun 17; 47(13):3388-98.JM

Abstract

The development of structure-activity relationships (SAR) with divergent classes of monoamine transporter ligands and comparison of their effects in animal models of cocaine abuse have provided insight into the complex relationship among structure, binding profiles, and behavioral activity. Many 3alpha-(diphenylmethoxy)tropane (benztropine) analogues are potent dopamine uptake inhibitors but exhibit behavioral profiles that differ from those of cocaine and other compounds in this class. One of the most potent and dopamine transporter (DAT) selective N-substituted benztropine analogues (N-(4-phenyl-n-butyl)-3alpha-(bis[4-fluorophenyl]methoxy)tropane, 1c) is devoid of cocaine-like behaviors in rodent models but is also highly lipophilic (cLogD = 5.01), which compromises its water solubility and may adversely affect its pharmacokinetic properties. To further explore the SAR in this series and ultimately to design dopamine uptake inhibitors with favorable lipophilicities for drug development, a comparative molecular field analysis (CoMFA) was performed on a set of benztropine analogues previously synthesized in our laboratory. The CoMFA field analysis on the statistically significant (r2(cv) = 0.632; r2(ncv) = 0.917) models provided valuable insight into the structural features required for optimal binding to the DAT, which was used to design a series of novel benztropine analogues with heteroatom substitutions at the tropane N-8. These compounds were evaluated for binding at DAT, serotonin (SERT) and norepinephrine (NET) transporters, and muscarinic M1 receptors in rat brain. Inhibition of [3H]DA uptake in synaptosomes was also evaluated. Most of the analogues showed high DAT affinity (12-50 nM), selectivity (10- to 120-fold), potent inhibition of dopamine uptake, and lower lipophilicities as predicted by cLogD values.

Authors+Show Affiliations

Medicinal Chemistry Section, National Institute on Drug Abuse--Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15189035

Citation

Kulkarni, Santosh S., et al. "Structure-activity Relationships at Monoamine Transporters for a Series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: Comparative Molecular Field Analysis, Synthesis, and Pharmacological Evaluation." Journal of Medicinal Chemistry, vol. 47, no. 13, 2004, pp. 3388-98.
Kulkarni SS, Grundt P, Kopajtic T, et al. Structure-activity relationships at monoamine transporters for a series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation. J Med Chem. 2004;47(13):3388-98.
Kulkarni, S. S., Grundt, P., Kopajtic, T., Katz, J. L., & Newman, A. H. (2004). Structure-activity relationships at monoamine transporters for a series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation. Journal of Medicinal Chemistry, 47(13), 3388-98.
Kulkarni SS, et al. Structure-activity Relationships at Monoamine Transporters for a Series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: Comparative Molecular Field Analysis, Synthesis, and Pharmacological Evaluation. J Med Chem. 2004 Jun 17;47(13):3388-98. PubMed PMID: 15189035.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-activity relationships at monoamine transporters for a series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation. AU - Kulkarni,Santosh S, AU - Grundt,Peter, AU - Kopajtic,Theresa, AU - Katz,Jonathan L, AU - Newman,Amy Hauck, PY - 2004/6/11/pubmed PY - 2004/7/10/medline PY - 2004/6/11/entrez SP - 3388 EP - 98 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 47 IS - 13 N2 - The development of structure-activity relationships (SAR) with divergent classes of monoamine transporter ligands and comparison of their effects in animal models of cocaine abuse have provided insight into the complex relationship among structure, binding profiles, and behavioral activity. Many 3alpha-(diphenylmethoxy)tropane (benztropine) analogues are potent dopamine uptake inhibitors but exhibit behavioral profiles that differ from those of cocaine and other compounds in this class. One of the most potent and dopamine transporter (DAT) selective N-substituted benztropine analogues (N-(4-phenyl-n-butyl)-3alpha-(bis[4-fluorophenyl]methoxy)tropane, 1c) is devoid of cocaine-like behaviors in rodent models but is also highly lipophilic (cLogD = 5.01), which compromises its water solubility and may adversely affect its pharmacokinetic properties. To further explore the SAR in this series and ultimately to design dopamine uptake inhibitors with favorable lipophilicities for drug development, a comparative molecular field analysis (CoMFA) was performed on a set of benztropine analogues previously synthesized in our laboratory. The CoMFA field analysis on the statistically significant (r2(cv) = 0.632; r2(ncv) = 0.917) models provided valuable insight into the structural features required for optimal binding to the DAT, which was used to design a series of novel benztropine analogues with heteroatom substitutions at the tropane N-8. These compounds were evaluated for binding at DAT, serotonin (SERT) and norepinephrine (NET) transporters, and muscarinic M1 receptors in rat brain. Inhibition of [3H]DA uptake in synaptosomes was also evaluated. Most of the analogues showed high DAT affinity (12-50 nM), selectivity (10- to 120-fold), potent inhibition of dopamine uptake, and lower lipophilicities as predicted by cLogD values. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/15189035/Structure_activity_relationships_at_monoamine_transporters_for_a_series_of_N_substituted_3alpha__bis[4_fluorophenyl]methoxy_tropanes:_comparative_molecular_field_analysis_synthesis_and_pharmacological_evaluation_ L2 - https://dx.doi.org/10.1021/jm030646c DB - PRIME DP - Unbound Medicine ER -