MEDICINAL CHEMISTRY APPLIED TO PROBLEMS PROMINENT IN SENESCENCE

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Alkylating prazosin, a compound which was prepared in the Section last year and which has the potential to bind permanently to adrenergic receptors of the alpha1 type, was presently evaluated. This compound was found to bind reversibly to all receptors of this type but permanent binding was established only to a fraction of them. The results show that alpha1- adrenoceptors are not a homogenous group and division of these into subgroups will be necessary. A carbostyril derivative which fully activated and permanently binds to beta-adrenoceptors was designed and synthesized. This compound pulls the trigger of receptors, which are in charge of the "fight or flight" reaction, and keeps the trigger pulled down for the duration. Work at the University of Florida established the correctness of the design. When beta-adrenoceptors were activated by this compound they could not be deactivated by the addition of a beta-blocker, a deactivation which occurred when natural, reversibly acting hormones were used for the activation. Testosterone in the circulation of mammals rises several fold above its background levels during episodes lasting a couple of hours and occurring daily. By administration of the water soluble pharmaceutical form of testosterone, developed in the Section, these episodes may be imitated. Researchers at the University of Missouri used this preparation to establish the importance of testosterone episodes for androgen-sensitive behavior and physiology.