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CoMFA study of novel phenyl ring-substituted 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter.
J Med Chem. 1999 Sep 09; 42(18):3502-9.JM

Abstract

A series of phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane (benztropine) has been prepared as novel probes for the dopamine transporter. Cross-validated comparative molecular field analysis (CoMFA) models of the binding domain on the dopamine transporter were constructed using 37 geometry-optimized structures of these compounds and their corresponding binding affinities (K(i) values) for the displacement of [(3)H]WIN 35,428 or potency of [(3)H]dopamine uptake inhibition (IC(50) values) in rat caudate putamen tissue. The most predictive model (q(2) = 0.78) correlated the steric component of CoMFA to the dependent variable of [(3)H]WIN 35,428 binding affinities. A novel series of seven phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane was prepared, and our best molecular model was used to accurately predict their binding affinities. This study is the first to provide a CoMFA model for this class of dopamine uptake inhibitors. This model represents an advancement in the design of novel dopamine transporter ligands, based on 3alpha-(diphenylmethoxy)tropane, and further substantiates structure-activity relationships that have previously been proposed for this class of compounds. This CoMFA model can now be used to predict the binding affinities of novel 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter and will be useful in the design of molecular probes within this class of dopamine uptake inhibitors.

Authors+Show Affiliations

Psychobiology 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 available

Pub Type(s)

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

Language

eng

PubMed ID

10479283

Citation

Newman, A H., et al. "CoMFA Study of Novel Phenyl Ring-substituted 3alpha-(diphenylmethoxy)tropane Analogues at the Dopamine Transporter." Journal of Medicinal Chemistry, vol. 42, no. 18, 1999, pp. 3502-9.
Newman AH, Izenwasser S, Robarge MJ, et al. CoMFA study of novel phenyl ring-substituted 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter. J Med Chem. 1999;42(18):3502-9.
Newman, A. H., Izenwasser, S., Robarge, M. J., & Kline, R. H. (1999). CoMFA study of novel phenyl ring-substituted 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter. Journal of Medicinal Chemistry, 42(18), 3502-9.
Newman AH, et al. CoMFA Study of Novel Phenyl Ring-substituted 3alpha-(diphenylmethoxy)tropane Analogues at the Dopamine Transporter. J Med Chem. 1999 Sep 9;42(18):3502-9. PubMed PMID: 10479283.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CoMFA study of novel phenyl ring-substituted 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter. AU - Newman,A H, AU - Izenwasser,S, AU - Robarge,M J, AU - Kline,R H, PY - 1999/9/10/pubmed PY - 1999/9/10/medline PY - 1999/9/10/entrez SP - 3502 EP - 9 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 42 IS - 18 N2 - A series of phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane (benztropine) has been prepared as novel probes for the dopamine transporter. Cross-validated comparative molecular field analysis (CoMFA) models of the binding domain on the dopamine transporter were constructed using 37 geometry-optimized structures of these compounds and their corresponding binding affinities (K(i) values) for the displacement of [(3)H]WIN 35,428 or potency of [(3)H]dopamine uptake inhibition (IC(50) values) in rat caudate putamen tissue. The most predictive model (q(2) = 0.78) correlated the steric component of CoMFA to the dependent variable of [(3)H]WIN 35,428 binding affinities. A novel series of seven phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane was prepared, and our best molecular model was used to accurately predict their binding affinities. This study is the first to provide a CoMFA model for this class of dopamine uptake inhibitors. This model represents an advancement in the design of novel dopamine transporter ligands, based on 3alpha-(diphenylmethoxy)tropane, and further substantiates structure-activity relationships that have previously been proposed for this class of compounds. This CoMFA model can now be used to predict the binding affinities of novel 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter and will be useful in the design of molecular probes within this class of dopamine uptake inhibitors. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/10479283/CoMFA_study_of_novel_phenyl_ring_substituted_3alpha__diphenylmethoxy_tropane_analogues_at_the_dopamine_transporter_ L2 - https://dx.doi.org/10.1021/jm980701v DB - PRIME DP - Unbound Medicine ER -