The metabolism in man of (3H)-5alpha-16-androsten-3alpha-ol and of (3H)-5alpha-16-androsten-3-one

The in vitro metabolism in man of two 16-androstene steroids, 5alpha-16-androsten-3-one and 5alpha-16-androsten-3alpha-ol, has been studied using 3H-labelled tracers. 4 healthy subjects (2 of each sex) were chosen, and each labelled steroid was administered, by a single injection, to 1 man and 1 woman. Disappearance of (3H)-3alpha-androstenol in the subjects receiving this compound followed a curve which indicated a two-pool distribution in both cases; metabolic clearance rates for these subjects were found to be 3,790 1/24 h in the man and 3,120 1/24 h in the woman. Blood production rates calculated for the 3alpha-androstenol-treated subjects were 875 microgram/24 h in the man and 1,780 microgram/24 h in the woman. Recovery of 3H in the urine of all 4 subjects was very low, between 28 and 42%. Conversion of the injected precursors to urinary 3alpha-androstenol was 13.5 and 12.7% in the 2 men and 6.1 and 5.9% in the 2 women. The male subjects were found to have a lower 24-hour urinary 3alpha-androstenol output (570 and 387 microgram/24 h) than the average for men of their age. The urinary 3alpha-androstenol output in the women was 225 and 276 microgram/24 h, and was within the normal range for women. The urine production rates of 3alpha-androstenol were 2,470 and 4,090 microgram/24 h in the male and female subjects, respectively; the difference between the blood and urine production rates of this compound are thought to indicate the direct secretion of conjugates. Urine production rates of 5alpha-androstenone (measured as 3alpha-androstenol) were 2,370 and 4,340 microgram/24 h in the male and female subjects, respectively.     

In vitro metabolism of 3beta-hydroxy-, and 3beta,14alpha-dihydroxy-[3alpha-3H]-5beta-cholest-7-en-6-one by the prothoracic glands of Manduca sexta.

alpha-Ecdysone (2beta,3beta,14alpha,22R,25-pentahydroxy-5beta-cholest-7-en-6-one) has been identified as the metabolism product of 3beta,14alpha-dihydroxy-5beta-cholest-7-en-6-one in isolated prothoracic glands of the tobacco hornworm, Manduca sexta. In contrast, 3beta-hydroxy-5beta-cholest-7-en-6-one is metabolized to 14-deoxy-alpha-ecdysone and a variety of intermediates all lacking the 14-hydroxy group. The results suggest that either the normal precursor for the synthesis of alpha-ecdysone by prothoracic glands is a sterol more highly oxygenated than cholesterol or that hydroxylation of a minimally oxygenated precursor at C-14 must precede introduction of the C-6 ketone and/or delta7 bond. The data further suggest that several alternative hydroxylation routes may exist for the latter steps of alpha-ecdysone biosynthesis.     

Synthesis of the allylic gonadal steroids, 3 alpha-hydroxy-4-pregnen-20-one and 3 alpha-hydroxy-4-androsten-17-one, and of 3 alpha-hydroxy-5 alpha-pregnan-20-one

A method for the convenient synthesis of the recently isolated allylic gonadal steroids, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha-dihydroprogesterone; 3 alpha-DHP) and 3 alpha-hydroxy-4-androsten-17-one (3 alpha-HA), was developed using 4-pregnene-3,20-dione (progesterone) and 4-androstene-3,17-dione as substrates and potassium trisiamylborohydride (KS-Selectride) as reducing agent. Similar reactions were also used for the reduction of 5 alpha-pregnane-3,20-dione to 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-HP). The yields were about 15%, 50%, and greater than 90% for 3 alpha-DHP, 3 alpha-HA and 3 alpha-HP, respectively. Structures of the products, including the 3 beta-isomers and the 17 alpha-epimer, formed in these reactions were determined by NMR and mass spectroscopic methods.     

Conversion of 5 alpha-pregnane-3,20-dione, 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 beta-hydroxy-5 alpha-pregnan-20-one to delta 16-C19 steroids by the reconstituted delta 16-C19-steroid synthetase system

The substrate specificity of the reconstituted delta 16-C19-steroid synthetase system, which catalyzes the formation of 5,16-androstadien-3 beta-ol or 4,16-androstadien-3-one from pregnenolone or progesterone, respectively, was studied. The reconstituted system consisted of a partially purified cytochrome P-450, NADPH-cytochrome P-450 reductase, cytochrome b5 and NADH-cytochrome b5 reductase all from pig testicular microsomes. It was found that 5 alpha-reduced C21 steroids such as 5 alpha-pregnane-3,20-dione, 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 beta-hydroxy-5 alpha-pregnan-20-one can be substrates for the enzyme system, resulting in the formation of 5 alpha-androst-16-en-3-one, 5 alpha-androst-16-en-3 alpha-ol and 5 alpha-androst-16-en-3 beta-ol, respectively. The results suggest that 5 alpha-reduced delta 16-C19 steroids might be synthesized from pregnenolone and progesterone via 5 alpha-reduced C21 steroids as intermediates. The pathways would bypass 5,16-androstadien-3 beta-ol and 4,16-androstadien-3-one which have been assumed as obligatory intermediates in the formation of 5 alpha-reduced delta 16-C19 steroids from pregnenolone and progesterone.     

N-acylated alpha-(3-pyridylmethyl)-beta-aminotetralin antagoinists of the human neuropeptide Y Y5 receptor

Alpha-(3-Pyridylmethyl)-beta-aminotetralins were acylated with amino-piperidinyl and-pyrrolidinyl acetic acids, and with (aminomethyl)cyclohexanecarboxylic acid. Reaction with acyl chlorides, chloroformates, and isocyanates gave amides 8e, carbamates 9, and ureas 10, which bound to the Y5 receptor with nanomolar affinity. Congeners 11a and 11d containing a terminal benzimidazolone group were shown to be functional Y5 antagonists.