Twenty-four thyrotropin-releasing hormone (TRH) analogues containing mainly aliphatic amino acids in position 2 were synthesized and tested for central nervous system (CNS) and hormonal (TSH) activity. Application of the pentafluorophenyl ester method in the syntheses resulted in optimal yields and high purity of the products. The neutral tripeptides pGlu- Nva -Pro-NH2 (9), pGlu-Nle-Pro-NH2 (10), and pGlu-Leu-Pro-NH2 (3) with a three- or four-membered straight or branched alkyl side chain in the position of the central amino acid had 2.5 to 10 times stronger anticataleptic effect than TRH, demonstrating that the presence of histidine is not essential for the CNS activity. Analogue 9 exhibited tenfold anticataleptic activity as compared to TRH, and it was found to be fully inactive in the release of TSH.

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A new series of thyrotropin-releasing hormone (TRH) analogues, obtained by further modifications of our most potent central nervous system (CNS) stimulating neutral tripeptides at both termini, were synthesized by the pentafluorophenyl ester method and tested for CNS and thyrotropin (TSH) releasing activity. Replacement of pyroglutamic acid by pyro-2-aminoadipic acid, 2-oxoimidazolidine-4-carboxylic acid or gamma-butyrolactone-gamma-carboxylic acid and that of proline by pipecolic acid, thiazolidine-4-carboxylic acid, or homoproline in [Leu2]- and [Nva2]TRH led to tripeptides structurally widely different from TRH. In spite of this fact, 7 of the 17 analogues (1, 2, 8-10, 16, and 17) have stronger anticataleptic effect than TRH, with negligible or no hormonal potency. The highest CNS activity was achieved when pyroglutamic acid was replaced by pyro-2-aminoadipic acid at the N-terminus [pAad-Leu-Pro-NH2, 1 (RGH 2202), and pAad-Nva-Pro-NH2,2]. A novel synthesis of L-2-aminoadipic acid suitable for large-scale preparation is also described.

Esters of the centrally acting oxazepam were investigated to find quantitative correlations between the pharmacokinetics of the parent drug and in vitro biotransformation rates and physicochemical properties of its prodrugs. The 14C-labeled aliphatic and omega-phenyl-substituted esters were administered intravenously to mice. Brain levels of the esters and oxazepam were determined and the latter was fitted to a simplified exponential equation. In vitro hydrolysis rate of the esters catalyzed by the hepatic microsomal fraction was measured with a pH stat. Pharmacokinetic constants characterizing the rising part of oxazepam brain levels correlate well with the chromatographic RM values and with in vitro maximal hydrolysis rates of the esters. The hydrolysis is capacity limited in the liver. In a closely related set of aliphatic esters, oxazepam brain penetration also correlates with the steric constant (ES) of its esters.

Vinpocetine (CavintonB), vincamine, and nicergoline (SermionB) were evaluated for the ability to protect cognitive function of spontaneously hypertensive rats from the damaging effect of hypoxia. Normobaric hypoxia (6% oxygen) was applied during the acquisition of a two-way active avoidance task (3 sessions, 50 trialsisession). Hypoxia decreased the percentage of conditioned avoidance responses by 50% on day 3. Vinpocetine (1.25-1 0 mg/kg) administered orally 60 min prior to the daily sessions did not significantly improve learning in normoxic conditions; however, it prevented hypoxia-induced learning deficit (1.25 mg/kg peak effect dose). The dose-response relationship for the compound is an inverted U-shaped curve. Vincamine (2.5-20 mgikg p.0.) did not facilitate learning under normoxic conditions, but afforded protection against hypoxia at the 20-mgikg dose. Nicergoline (2.5-20 mg/kg p.0.) did not increase acquisition of the normoxic avoidance response, and it also showed a moderate antihypoxic effect. Vinpocetine, and to a lesser degree vincamine and nicergoline-drugs useful in the therapy of cognitive disturbances following cerebral ischemichypoxic states-proved effective in the prevention of a hypoxia-induced learning deficit.