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3'-Chloro-3 alpha-(diphenylmethoxy)tropane but not 4'-chloro-3 alpha-(diphenylmethoxy)tropane produces a cocaine-like behavioral profile.
J Med Chem. 1997 Mar 14; 40(6):851-7.JM

Abstract

A series of 2'- and 3'-substituted and 3',3"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (Ki). Generally, meta-substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported para-substituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same meta-substituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K1 = 0.41-2.52 nM). Interestingly, 3'-chloro-3 alpha-(diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment.

Authors+Show Affiliations

Psychobiology Section, National Institutes of Health, National Institute on Drug Abuse-Division of Intramural Research, Baltimore, Maryland 21224, USA.No affiliation info availableNo 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

9083473

Citation

Kline, R H., et al. "3'-Chloro-3 Alpha-(diphenylmethoxy)tropane but Not 4'-chloro-3 Alpha-(diphenylmethoxy)tropane Produces a Cocaine-like Behavioral Profile." Journal of Medicinal Chemistry, vol. 40, no. 6, 1997, pp. 851-7.
Kline RH, Izenwasser S, Katz JL, et al. 3'-Chloro-3 alpha-(diphenylmethoxy)tropane but not 4'-chloro-3 alpha-(diphenylmethoxy)tropane produces a cocaine-like behavioral profile. J Med Chem. 1997;40(6):851-7.
Kline, R. H., Izenwasser, S., Katz, J. L., Joseph, D. B., Bowen, W. D., & Newman, A. H. (1997). 3'-Chloro-3 alpha-(diphenylmethoxy)tropane but not 4'-chloro-3 alpha-(diphenylmethoxy)tropane produces a cocaine-like behavioral profile. Journal of Medicinal Chemistry, 40(6), 851-7.
Kline RH, et al. 3'-Chloro-3 Alpha-(diphenylmethoxy)tropane but Not 4'-chloro-3 Alpha-(diphenylmethoxy)tropane Produces a Cocaine-like Behavioral Profile. J Med Chem. 1997 Mar 14;40(6):851-7. PubMed PMID: 9083473.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3'-Chloro-3 alpha-(diphenylmethoxy)tropane but not 4'-chloro-3 alpha-(diphenylmethoxy)tropane produces a cocaine-like behavioral profile. AU - Kline,R H, AU - Izenwasser,S, AU - Katz,J L, AU - Joseph,D B, AU - Bowen,W D, AU - Newman,A H, PY - 1997/3/14/pubmed PY - 1997/3/14/medline PY - 1997/3/14/entrez SP - 851 EP - 7 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 40 IS - 6 N2 - A series of 2'- and 3'-substituted and 3',3"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (Ki). Generally, meta-substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported para-substituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same meta-substituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K1 = 0.41-2.52 nM). Interestingly, 3'-chloro-3 alpha-(diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9083473/3'_Chloro_3_alpha__diphenylmethoxy_tropane_but_not_4'_chloro_3_alpha__diphenylmethoxy_tropane_produces_a_cocaine_like_behavioral_profile_ L2 - https://dx.doi.org/10.1021/jm950782k DB - PRIME DP - Unbound Medicine ER -