Structure-activity relationships of steroid hormones on muscarinic receptor binding

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Abstract

A total of fifty steroidal compounds were tested for their inhibition on the binding of muscarinic receptor antagonist, [3H]quinuclidinyl benzilate ([3H](−)QNB), to the hypothalamic membranes prepared from male rats. Among the compounds tested, the active structures (with IC50 values ⩽100 μM in parentheses) are: progesterone (40), 5β-pregnane-3,20-dione (40), deoxycorticosterone (50), 5β-pregnane-17α,21-diol-3,20-dione (30), 11-desoxy-17-hydroxycorticosterone (22), 17α-hydroxyprogesterone (20), 5β-pregnan-17α-ol-3,20-dione (24), 5β-androstane-3,17-dione (100), and 5β-dihydrotestosterone (100). By examining all the compounds tested, the following structure-activity relationship became apparent: (a) The ring A-reduced steroidal structures with a 5β -conformation were more potent than those with a 5α-conformation; (b) 17α-hydroxylation of the steroidal ring increased the steroid's inhibitory activity; (c) The C3 carbonyl group was essential for activity; (d) Reduction of the C3 carbonyl group or aromatization of the ring A abolished the steroid's inhibitory activity; (e) Oxidation of the C11 position of ring C resulted in a decrease or loss of inhibitory activity; and (f) Different modifications of the side chain of ring D by acetylation resulted in either an increase or a decrease in the inhibitory activity. The structure-activity relationship as revealed in this study might provide an insight for the synthesis of a steroidal molecule with a high affinity for the muscarinic receptor as well as for the search of a more potent and physiologically relevant steroidal metabolite possessing the ability to interact with the muscarinic receptor.

References (49)

  • L.G. Clemens et al.

    Cholinergic brain mechanism and the hormonal regulation of female sexual behavior in the rat

    Pharmac. Biochem. Behav.

    (1980)
  • L.G. Clemens et al.

    Inhibition of lordotic behavior in female rats following intracerebral infusion of anticholinergic agents

    Pharmac. Biochem. Behav.

    (1980)
  • O.H. Lowry et al.

    Protein measurements with the Folin phenol reagent

    J. biol. Chem.

    (1951)
  • B.T. Donovan

    Hormones and Human Behavior

  • H.H. Feder

    Hormones and sexual behavior

    A. Rev. Psychol.

    (1984)
  • W.F. Riker et al.

    Electro-physiological and clinical aspects of glucocorticoids in central neural systems

  • B. Bohus et al.

    Adrenal steroids and behavioral actaptation: relationship to brain corticoid

  • R.M. Rose

    Psychoendocrinology

  • R.T. Rubin et al.

    Postnatal gonadal steroid effects on human behavior

    Science

    (1981)
  • D.M. Woodbury

    Relation between the adrenal cortex and the central nervous system

    Pharmac. Rev.

    (1958)
  • I.M. Davidson

    Feedback regulation of gonadotropin secretion

  • B.C. Little et al.

    Physiological and psychological effects of progesterone in man

    J. Nerv. men. Dis.

    (1974)
  • R.M. Rose

    The psychological effects of androgens and estrogens—a review

  • E.L. Klaiber et al.

    Estrogen therapy for severe persistent depressions in women

    Arch. Gen. Psychiat.

    (1979)
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    Present address: Department of Pharmacology, Pramongkutklao College of Medicine, Rajavithi Road, Bangkok, Thailand, 10400.

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