Biomedical subjects
Publications and source records attributed to N H Grant.
N-[[[(5-chloro-2-benzothiazolyl)thiolphenyllacetyll-L-cysteine (WY-45,368) is a potent inhibitor of human skin fibroblast collagenase. Kinetic data show that the inhibition is competitive, with a Ki of 3.5 microM. WY-45,368 inhibits neither of two other metalloproteinases, thermolysin and angiotensin converting enzyme, nor does it inhibit clostridial collagenase--thus indicating specificity for mammalian collagenase.
Proliferation of B lymphocytes is depressed in Lewis lung tumor bearing mice. Treatment of these mice with Wy-18,251 (5 mg/kg) significantly increased the responsiveness of their splenic T cells to concanavalin A in cell culture. Levamisole (5 mg/kg) acted more weakly than Wy-18,251. Neither Wy-18,251 nor levamisole elevated the depressed B cell mitogenesis. Wy-18,251 significantly increased macrophage phagocytosis against 51chromium labeled opsonized chicken red blood cells. Levamisole behaved differently: it either had no effect on phagocytosis, or depressed it.
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A nonreducible cyclic analog of somatostatin (SRIF) was prepared by a combination of solid phase and solution peptide synthesis. The compound, gamma-Abu-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Asp-OH, was tested for its effect on the release of growth hormone, glucagon and insulin in rats. It significantly suppressed pentobarbital-stimulated growth hormone release but showed no effect on arginine-stimulated glucagon or insulin release. The linear form, NH2-gamma-Abu-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Asp-OH, was also prepared and tested in vivo. It was shown to have only slight activity.
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Seven synthetic analogues of somatostatin helped clarify structural requirements for suppression of growth hormone secretion in rats. Size of the ring is not critical; deletions of serine-13, lysine-4 or asparagine-5 result in peptides which retain an appreciable fraction of the activity. The analogue des-Ala1, Gly2, Asn5-somatostatin lowers plasma growth hormone and insulin levels without affecting plasma glucagon levels significantly.
Two varients of LH-RH, less than Glu-D-Phe-Trp-D-Ala-Leu-Arg-Pro-Gly-NH2 (I) and less than Glu-D-Phe-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-NHCH2CH3 (II), have been synthesized by solid-phase methods. Both peptides strongly inhibit the LH-RH induced secretion of LH in an in vitro assay; however, only I proved effective in preventing ovulation in the 4-day cycling rat.
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An enzymatic system has been developed for the production of prostaglandin E(2) (PGE(2)) from arachidonic acid by extracts of sheep seminal vesicular glands. The presence of glutathione insures high yields. A new procedure for the purification of PGE(2) was also developed, based on the dialysis of the biosynthesized product at pH 8 and extraction of the dialysate at pH 3 with chloroform. This procedure routinely gives yields of PGE(2) of 25-37% (from arachidonic acid) with a purity of 90-100%. Additional analytical proof of the identity of PGE(2) was provided by physicochemical characteristics of the crystalline thiosemicarbazide derivative, which can be readily prepared under mild conditions.