Dose-response studies of penicillamine and related compounds in reducing skin—Tensile strength of rats

Abstract

Penicillamine (I) and certain related compounds are known to reduce the skin tensile strength (sts) of rat dorsal skin when they are given in the diet. This effect seems significant to studies of the biochemistry of collagen and of diseases of collagen, perhaps including the arthritides. The reduction of sts appears to be caused by diminution of collagen crosslinking. The effects of several such compounds were studied after intraperitoneal (ip) injection, in order to determine structure-activity relationships divorced from possible anorexic or gastrointestinal complications seen after oral dosing, and to examine the relation of ip dose to response. A cyclopentyl analog (II) of I was at least as active as I, showing that structural variants of I can be active when given ip. A dimethylthiazolidine (V) and a zinc chelate (III, rather toxic) of I were nearly as active as I, showing that probable in vivo precursors of I can be obtained that will be active when given ip. The disulfide of I and a zinc chelate of cysteine were inactive. Maximum response for several compounds seemed to occur at intermediate dose levels, with larger or smaller doses affording less sts reduction.