Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man.

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting. Rather, sweating and hypersalivation, mediated through muscarinic receptors, occurred dose-dependently and were finally dose-limiting. In contrast to talsaclidine, sabcomeline had a less pronounced functional M1 selectivity in pharmacological assays. This was also shown in anaesthetized guinea pigs where sabcomeline alone induced bronchoconstriction, and in the rabbit EEG where central activation and cholinergic side effects occurred in the same dose range. Neither drug, however, showed convincing improvement of cognitive functions in patients with mild-to-moderate Alzheimer's disease. This asks for a reassessment of the muscarinic hypothesis for the treatment of this disease.

Treatment with the selective muscarinic agonist talsaclidine decreases cerebrospinal fluid levels of total amyloid beta-peptide in patients with Alzheimer's disease.

Brain amyloid load in Alzheimer's disease (AD) is, at least in genetic forms, associated with overproduction of amyloid beta-peptides (A beta). Thus, lowering A beta production is a central therapeutic target in AD and may be achieved by modulating such key enzymes of amyloid precursor protein (APP) processing as beta-, gamma-, and alpha-secretase activities. Talsaclidine is a selective muscarinic M1 agonist that stimulates the nonamyloidogenic alpha-secretase pathway in model systems. Talsaclidine was administered double-blind, placebo-controlled, and randomized to 24 AD patients and cerebrospinal fluid (CSF) levels of total A beta were quantitated before and after 4 weeks of drug treatment. We observed that talsaclidine decreases CSF levels of A beta significantly over time within the treatment group (n = 20) by a median of 16% as well as compared to placebo (n = 4) by a median of 27%. We conclude that treatment with selective M1 agonists may reduce A beta production and may thus be further evaluated as a potential amyloid-lowering therapy of AD.

[Haemodynamic investigations with the new antihypertensive drug guanfacine (author's transl)]. / Hämodynamische Untersuchungen mit dem neuen Antihypertensivum Guanfacin. Kreislaufverhalten bei Hypertonikern im Akut- und Langzeitversuch, in Ruhe und unter Belastung.

Guanfacine, a new centrally acting alpha-mimetic antihypertensive drug, was given to two groups of 7 patients each, one with essential and the other with renal hypertension. Both in the acute trial (after short-term intermittent initial blood pressure increase) and in the long-term treatment (4 weeks) lowering of blood pressure occurred, mediated via decrease of peripheral vascular resistance. In addition, support of cardiac function, especially of the afterload and possibly also the preload, was induced. This was demonstrated by results obtained after ergometric loading.

[A new antihypertensive agent used in a clinical setting]. / Ein neues Antihypertensivum, angewendet unter Praxisbedingungen.

In a multicenter study with 54 patients with essential and renal hypertension (WHO I to III) the antihypertensive efficacy and safety of guanfacine were evaluated against clonidine in a double blind cross-over design. The treatment period for each drug lasted five weeks. There was a two week's wash-out period with placebo between the application of the respective preparations. During the first two weeks of treatment a daily dose of 3.3 mg guanfacine and 0.5 mg clonidine led to a significant fall in blood pressure from 187/103/138 mm Hg (s/d/m) to 152/86/113 mm Hg and from 186/101/136 mm Hg to 156/91/118 mm Hg respectively. During the following time blood pressure and dosage remained almost unchanged. In contrast to clonidine the guanfacine group showed a smaller fall in blood pressure in upright than in supine position. Both drugs showed a decrease of heart rate by approximately 4 beats per minute. Side effects such as dry mouth and tiredness were more pronounced under treatment with clonidine than with guanfacine (p less than or equal to 0,08). Guanfacine is well tolerated as a potential antihypertensive drug with relatively few side effects of mild nature.

Differences in psychic performance with guanfacine and clonidine in normotensive subjects.

1. Doses of clonidine 0.15 mg or guanfacine 1.0 mg, respectively, and 2 h later additional doses of clonidine 0.3 mg or guanfacine 2.0 mg, respectively, were given to 24 healthy students. 2. Blood pressure was reduced by the same amount by both drugs. 3. Plasma noradrenaline concentrations decreased with both drugs, but the reduction was significantly greater following the administration of clonidine. 4. Mental activity in the EEG was less suppressed in the guanfacine group than in the clonidine group. The differences were statistically significant. 5. Self-estimations for well-being and mood showed only small changes due to guanfacine but significant changes due to clonidine. 6. The decrease of information processing and the increase in reaction time, measured by performance in different psychometric tests, were significantly more pronounced after clonidine treatment than guanfacine. 7. A dose-response relationship could only be observed in vigilosomnograms, in the tests of self-estimation related to well-being and mood and in the decrease in plasma noradrenaline in the clonidine group. 8. It was concluded that guanfacine had a lesser CNS depressant action than clonidine, when administered in equipotent hypotensive doses.

[Synthesis of a fragment of the active center of the streptococcal proteinase (EC 3.4.22.10), IX]. / Synthese einer Partialsequenz aus dem aktiven Zentrum der Streptokokken-Proteinase (EC 3.4.22.10), IX

The synthesis of the protected pentapeptide tert-butyloxycarbonly-Gln-Ile-Met-Lys(X)-Gly-p-nitrobenzylester (X = benzyloxycarbonyl, 3-chlor-benzyloxycarbonyl) which is part of the carboxylend of a partial sequence of the active center of the streptococcal proteinase is described. Side reactions are observed if the tert-butyloxycarbonyl-protective group is cleaved by trifluoroacetic acid, not with HC1/dioxane. Obviously the presence of methionine is responsible for the formation of by products. Formation of methioninesulfoxide of tert-butylsulfoniummethionine could not be proved. tert-butyloxycarbonyl-Gln-1-hydroxybenzotriazolylester was obtained in a crystalline state from the reaction of tert-butyloxycarbonyl-Gln, dicyclohexylcarbodiimid and 1-hydroxybenzotriazol.

[Synthesis of a fragment of the active center of the streptococcal proteinase (EC 3.4.22.10), VIII (author's transl)]. / Synthese einer Partialsequenz aus dem aktiven Zentrum der Streptokokken-Proteinase (EC 3.4.22.10), VIII

The synthesis of the protected tricosapeptide Z-Val-Lys(Z)-Pro-Gly-Glu(OBzl)-Gln-Ser-Phe-Val-Gly-Gln-Ala-Ala-Thr-Gly-His-Cys(MBzl)-Val-Ala-Thr-Ala-Thr-Ala-ONB is described. The tricosapeptide was built up from the decapeptide Z-Val-Lys(Z)-Pro-Gly-Glu(OBzl)-Gln-Ser-Phe-Val-Gly-ONp and the tridecapeptideester Gln-Ala-Ala-Thr-Gly-His-Cys(MBzl)-Val-Ala-Thr-Ala-Thr-Ala-ONB. A further nonadecapeptide with tert-butylmercapto protection of the SH group was also synthetized.

[Synthesis of a fragment of the active center of the streptococcal proteinase (EC 3.4.22.10), VI (author's transl)]. / Synthese einer Partialsequenz aus dem aktiven Zentrum der Streptokokken-Proteinase (EC 3.4.22.10), VI

The synthesis and properties of the protected peptide Boc-His(Boc)-Cys(X)-Val-OH(ONP) [X = tert-butylmercapto, p-methoxybenzyl, tetrahydropyranyl-(2)] are described. This peptide is a fragment of an active center sequence of the streptococcal proteinase (EC 3.4.22.10) containing the essential SH group of the enzyme.

[Synthesis of a fragment of the active center of the streptococcal proteinase (EC 3.4.22.10), VII (author's transl)]. / Synthese einer Partialsequenz aus dem aktiven Zentrum der Streptokokken-Proteinase (EC 3.4.22.10), VII

The synthesis of the protected peptides Boc-Ala-Ala-Thr-Gly-ONp, Boc-Ala-Thr-Ala-Thr-Ala-ONB and Boc-Ala-Ala-Thr-Gly-His-Cys(X)-Val-Ala-Thr-Ala-Thr-Ala-ONB [X = p-methoxybenzyl, tert-butylmercapto, tetrahydropyranyl-(2)] is described. These peptides are fragments of an active center sequence of the streptococcal proteinase (EC 3.4.22.10) which contains the essential SH group of the enzyme.