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Research ArticleBehavioral Pharmacology

Novel Antimuscarinic Antidepressant-like Compounds with Reduced Effects on Cognition

Chad R. Johnson, Brian D. Kangas, Emily M. Jutkiewicz, Gail Winger, Jack Bergman, Andrew Coop and James H. Woods
Journal of Pharmacology and Experimental Therapeutics June 2021, 377 (3) 336-345; DOI: https://doi.org/10.1124/jpet.120.000337
Chad R. Johnson
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (C.R.J., A.C.); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (E.M.J.); Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (G.W., J.H.W.)
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Brian D. Kangas
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (C.R.J., A.C.); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (E.M.J.); Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (G.W., J.H.W.)
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Emily M. Jutkiewicz
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (C.R.J., A.C.); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (E.M.J.); Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (G.W., J.H.W.)
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Gail Winger
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (C.R.J., A.C.); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (E.M.J.); Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (G.W., J.H.W.)
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Jack Bergman
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (C.R.J., A.C.); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (E.M.J.); Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (G.W., J.H.W.)
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Andrew Coop
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (C.R.J., A.C.); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (E.M.J.); Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (G.W., J.H.W.)
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James H. Woods
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland (C.R.J., A.C.); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (E.M.J.); Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (G.W., J.H.W.)
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Abstract

The cholinergic nervous system has been implicated in mood disorders, evident in the fast-onset antidepressant effects of scopolamine, a potent muscarinic antagonist, in clinical studies. One prominent disadvantage of the use of scopolamine in the treatment of depression is its detrimental effects on cognition, especially as such effects might aggravate cognitive deficits that occur with depression itself. Thus, the identification of antimuscarinic drugs that are free of such detrimental effects may provide an important avenue for the development of novel therapeutics for the management of depression. The present data in rats indicate that a historical muscarinic antagonist, L-687,306, and a muscarinic antagonist of our own design, CJ2100, were as or more effective than scopolamine in antagonizing both the bradycardic effects of the muscarinic agonist arecoline in cardiovascular studies and its discriminative stimulus and rate-decreasing effects in behavioral studies. Additionally, both novel muscarinic antagonists were as effective as scopolamine in decreasing immobility in the forced swim test, a preclinical indicator of potential antidepressant activity. However, at equieffective or even larger doses, they were considerably less disruptive than scopolamine in assays of cognition-related behavior. All three drugs displayed high specificity for the mAChRs with few off-target binding sites, and CJ2100 showed modest affinity across the mAChRs when compared with L-687,306 and scopolamine. These data emphasize the dissimilar pharmacological profiles that are evident across antimuscarinic compounds and the potential utility of novel antagonists for the improved treatment of depression.

SIGNIFICANCE STATEMENT Some clinical studies with the muscarinic antagonist scopolamine document its ability to produce antidepressant effects in patients with mood disorders; however, scopolamine also has well known adverse effects on both autonomic and centrally mediated physiological functions that limit its therapeutic use. This study characterizes the cardiovascular and discriminative stimulus effects of two novel muscarinic antagonists, L-687,306 and CJ2100, that produce antidepressant-like effects in a rodent model (forced swim test) without affecting touchscreen-based cognitive performance (titrating psychomotor vigilance and delayed matching-to-position).

Footnotes

    • Received September 15, 2020.
    • Accepted March 9, 2021.
  • Funding for the research was provided by National Institutes of Health National Institute of Mental Health [Grant R01-MH107499].

  • The authors are coholders of a pending United States patent on CJ2100 (PCT/US2020/026802) and declare no other conflicts of interest.

  • https://doi.org/10.1124/jpet.120.000337.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 3
1 Jun 2021
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Research ArticleBehavioral Pharmacology

Antimuscarinic Compounds with Reduced Effects on Cognition

Chad R. Johnson, Brian D. Kangas, Emily M. Jutkiewicz, Gail Winger, Jack Bergman, Andrew Coop and James H. Woods
Journal of Pharmacology and Experimental Therapeutics June 1, 2021, 377 (3) 336-345; DOI: https://doi.org/10.1124/jpet.120.000337

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Research ArticleBehavioral Pharmacology

Antimuscarinic Compounds with Reduced Effects on Cognition

Chad R. Johnson, Brian D. Kangas, Emily M. Jutkiewicz, Gail Winger, Jack Bergman, Andrew Coop and James H. Woods
Journal of Pharmacology and Experimental Therapeutics June 1, 2021, 377 (3) 336-345; DOI: https://doi.org/10.1124/jpet.120.000337
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