Introduction of steroids

Dr.Sanaa Bardaweel

Steroid hormone receptors

• Steroid receptors are proteins found in the cytoplasm or nucleus of eukaryotic cells which bind to and regulate the transcription of DNA under the regulation of steroid hormones.

• Steroid receptors (proteins) share regions of close structural and/or functional homology which are called domains.

Type I Receptors • Sex hormone receptors (sex hormones) • Androgen receptor • Estrogen receptor • Progesterone receptor • Glucocorticoid receptor (glucocorticoids) • Mineralocorticoid receptor (mineralocorticoids)

Type II Receptors • Vitamin A receptor (Vitamin A) • Vitamin D receptor (Vitamin D) • Retinoid receptor • Thyroid hormone receptor • Orphan receptors

Steroid skeleton. Carbons 18 and above can be absent.

mineralocorticoids: Aldosterone

• Mineralcorticoids maintain salt balance • stimulates the kidney to conserve sodium (Na+) and excrete

potassium (K+) and hydronium (H+ = H3O+) cations. Aldosterone levels increase during the process of acclimation to hot climates

• Aldosterone release is stimulated by ACTH from the anterior pituitary, angiotensin II from the kidney, and an increase in the relative ratio of K+/Na+.

• Functional groups essential for aldosterone activity: • -double bond at D4 • -C3 ketone • -C20 ketone

Glucocorticoids: Cortisol

• Glucocorticoids maintain glucose availability. Cortisol acts mainly on the liver, with muscle and brain as secondary targets.

• Cortisol can stimulate de-novo synthesis of glucose, conversion of amino acids into glucose, or release of glucose from glycogen storage. (Catabolic)

• Functional groups essential for glucocorticoid activity: • C21 hydroxyl • C11 hydroxyl

Steroid analogs with antiinflammatory activity: Prednisolone

• Add fluorine to C9. 9-a-fluorocortisol has 10 times more activity compared to the parent cortisol.

• However, it also has 125 times the mineralcorticoid activity, so considerable specificity is lost!

• Add double bond at C1. five times more active than their parent compound cortisol respectively, without changing mineralcorticoid activity.

• Add a C16 methyl group. A methyl group added to either the a or b face increases glucocorticoid activity and decreases mineralcorticoid activity for overall increased selectivity.

Glucocorticoids: Cortisol

• Glucocorticoids maintain glucose availability. Cortisol acts mainly on the liver, with muscle and brain as secondary targets.

• Cortisol can stimulate de-novo synthesis of glucose, conversion of amino acids into glucose, or release of glucose from glycogen storage. (Catabolic)

• Functional groups essential for glucocorticoid activity: • C21 hydroxyl • C11 hydroxyl

•Mechanism of action: increased the resistance to stress, decrease white blood cells and inhibit COX (anti-inflammatory)•Therapeutic uses: Addison’s disease (low glucocorticosteroids) and anti-inflammatory, Txt of allergy and accelerate lung maturation (especially Beclomethasone).•Side effects: negative calcium balance, impaired wound healing, increase appetite, hypertension, emotional disturbances, odema, peptic ulcer, glaucoma, hypokalemia, hirsutism and moon face.

Cortisol(hydrocortisone)

•Mechanism of action: inactive form of Cortisol.•Prodrug, HSD1,2

Cortisone

Steroid analogs with antiinflammatory activity: Prednisolone

• Add fluorine to C9. 9-a-fluorocortisol has 10 times more activity compared to the parent cortisol.

• However, it also has 125 times the mineralcorticoid activity, so considerable specificity is lost!

• Add double bond at C1. five times more active than their parent compound cortisol respectively, without changing mineralcorticoid activity.

• Add a C16 methyl group. A methyl group added to either the a or b face increases glucocorticoid activity and decreases mineralcorticoid activity for overall increased selectivity.

•Mechanism of action: the active metabolite of Prednisone•Therapeutic uses: intermediate acting anti-inflammatory.

Prednisolone

•Therapeutic uses: intermediate acting anti-inflammatory.•Ring A: 2 DB..Selective Anti-inflammatory .

•Oral rout, TN

Prednisone

Methylprednisolone

•Therapeutic uses: anti-inflammatory used for COPD.•2DB•F: safe halogen, increase Anti-inflammatory effect, increase t.5.•NO mineralcorticoid activity.•OH instead of CH3 (C16) short duration

Triamcinolone

•Therapeutic uses: long acting anti-inflammatory.•2DB, F•Betamethasone has 25 times more activity as antiinflammatory than cortisol•NO mineralcorticoid activity.

Betamethasone

•Therapeutic uses: long acting anti-inflammatory.•Methyl on ring D

• dexamethasone has 30 times the activity of cortisol.•NO mineralcorticoid activity.

Dexamethasone

•Therapeutic uses: anti-inflammatory with very high mineralocorticoid activity.

Fludrocortisone

•Therapeutic uses: anti-inflammatory used in inhalers of COPD.•Ester, increase absorption from alveoli.

Beclometasone dipropionate (Clenil)

mineralocorticoids: Aldosterone

• Mineralcorticoids maintain salt balance • stimulates the kidney to conserve sodium (Na+) and excrete

potassium (K+) and hydronium (H+ = H3O+) cations. Aldosterone levels increase during the process of acclimation to hot climates

• Aldosterone release is stimulated by ACTH from the anterior pituitary, angiotensin II from the kidney, and an increase in the relative ratio of K+/Na+.

• Functional groups essential for aldosterone activity: • -double bond at D4 • -C3 ketone • -C20 ketone

•Mechanism of action: compete with aldosterone action (Antagonist)•Therapeutic uses: anti-hypertensive. Used for txt of hirsutism in women.•Side effects: hyperkalemia.•called potassium-sparing diuretics

Spironolactone

•Mechanism of action: inhibit 11-hydroxylation of steroid(Enzyme inhibitor of HSD)•Reduces Cortisol • Therapeutic uses: decrease insulin resistance (in obese)•Side effects: water retention and hirsutism (more cortisone available for other steroid synthesis)

Metyrapone

Androgens: Testosterone

• 17-b-OH (hydroxyl) and a 3-keto group are necessary for activity.

• The primary site of testosterone synthesis is the testes (Leydig cells) with low level synthesis occurring in the adrenal cortex. Low levels of testosterone are also synthesized in the ovary.

Androgens• Development of male sex characteristics, both fetal and at puberty, ongoing

spermatogenesis, and maintenance of male characteristics. • Increased muscle mass and protein synthesis. (Anabolic)

• By a long feed-back loop, testosterone inhibits its own synthesis by acting upon the hypothalamus to turn off LHRH (leutinizing hormone releasing hormone) secretion. (Impotence)

No OH at C-11 So no anti-inflammatory or mineral effect

Testosterone

Testosterone Antagonists: Flutamide

• Potential treatments for prostate cancer or acne Flutamide inhibits both androgen uptake and binding in target tissue.

Oral nonsteroidal antiandrogen drug

Estrogens and progestins• Estrogens target the ovarian follicle and maintain female sex

characteristics. • Estrogens are primarily secreted by the ovary, but during the first

months of pregnancy, most of the estrogen comes from the ruptured follicle and corpus luteum. During the latter months of pregnancy, most estrogen comes from the placenta.

• There are three classic estrogens, estrone, 17-b estradiol (most potent), and estriol.

• The main uses for synthetic estrogens are in contraception and in the maintenance of female reproductive endothelial integrity.

• Unlike testosterone, estrogen lacks a C19 methyl group and the A ring is aromatic and consequentially planar. Most changes to the estrogen structure cause a loss of activity, such as conversion at position 3 of -OH (hydroxyl) to =O (carbonyl) or addition of side chains at positions 3.

• Estrogen antagonists are used to treat estrogen-dependent breast cancer in postmenopausal women (67% of breast cancer is estrogen-dependent).

• Antagonists can also be used as fertility drugs by blocking estrogen feedback to the anterior pituitary.

• Examples of estrogen antagonists inspired initially from nonsteroidal plant compounds called stilbenes include the anticancer agent Tamoxifen and the anti-infertility drug Clomiphene.