Studies on the peripheral and central pharmacological activity of a series of synthetic nitrogenous steroids

Ross, Hugh H (1967) Studies on the peripheral and central pharmacological activity of a series of synthetic nitrogenous steroids. MSc(R) thesis, University of Glasgow.

Abstract

A study has been made of the phamacological properties of 26 nitrogenous steroids, with particular reference to their effects on the central nervous system. The results are discussed in toms of possible correlations between chemical structure and biological activity. Twenty-three of the compounds under investigation were androstanes or pregnanes bearing a substituted amino group in the 2beta- or 3alpha- position. Two of the remaining compounds carried an amino substituent at either the 6alpha- position (compound Al8), or at the 17beta- position (compound A25) whilst the material designated compound A7 was in fact an equilibrium mixture of 2alpha-morpholino-5alpha-androstane-3,17-dione and 2beta-morpholino-5alpha-androstane-3,17-dione. The compounds were investigated in mice for general anaesthetic and anti-Parkinsonian activity and also for their ability to induce loss of the righting reflex and to antagonize electrically- and chemically-induced seizures. In addition, the effects of the compounds on blood pressure and on neuromuscular and ganglionic transmission in the anaesthetized cat were investigated as were their effects on a polysynaptic preparation of the spinalized cat. Three of the coupounds (A12, A17 and A24) on intravenous administration to nice, induced loss of the righting reflex and this effect was attributed to the possession of interneuronal blocking activity by these conpounds. With respect to anticonvulsant activity, none of the compounds gave protection against electrically- induced seizures without the simultaneous presence of side effects such as excitation, sedation and/or loss of the righting reflex while, apart from one example (compound A24), no compound was active against leptazol-induced seizures. From these results it has been concluded that anticonvulsant activity is not a specific property of the compounds under investigation. None of the compounds investigated produced a degree of anaesthesia sufficient for surgery nor did they antagonize the tremors induced by tremorine, the latter result suggesting the absence of anti-Parkinsonian activity. It was observed that anticonvulsant activity and ability to induce loss of the righting reflex appeared to be associated more with conpounds which have the nitrogenous radical in the 2beta- position than with conpounds which have the nitrogen function in the 3alpha- position and that the presence of additional nuclear substituents appeared to diminish the power to induce loss of the righting reflex. A total of ton 2beta- and 3alpha-monoquaternary armonium steroids of the androstane and pregnano types, as well as a single bisquaternary annoniun androstane have been investigated for neuromuscular blocking activity. The results are again discussed in terms of possible structure-action relationships. The evaluation of the muscle relaxant activity of the compounds studied was carried out employing conventional techniques with the oat and the hen gastrocnemius muscle- sciatic nerve preparations, the rat phrenic nerve-diaphragm preparation and the frog rectus abdominis muscle preparation. Toxicity tests on nice were also conducted as were studies of the effects of the compounds on autonomic ganglia in the cat and the guinea pig and on respiratory musculature in the cat and the rabbit. Applying the accepted criteria for the qualitative differentiation of depolarizing and non-depolarising activity, all eleven compounds were shown to display typical non-depolarizing activity. In both the cat and the hen, the time of onset of maxim.um paralysis and the duration of block was significantly less than, those for tubocurarine. In all species examined, with the exception of the frog, the activity of the ten monoquaternary ammonium steroids as muscle relaxants proved very low and all were considerably less potent than tubocurarine. The most active compound (B1) was only 1/16th as active on the cat as tuboourarine on a molar basis. Differences in potency between the various monoquaternary ammoniun steroids have been interpreted as arising from variations in the nitrogen substituents rather than from alterations in hydrophilic to lipophilic balance. The one bisquaternary steroid under examination (compound B11) showed potency comparable to or greater than that of tubocurarine in all species, except the mouse. Consideration of the activity of this compound in terms of the activities of other steroidal bisquaternary ammonium salts already reported in the literature has been taken to indicate the relative unimportance of a "fixed" interonium distance in determining neuromuscular blocking activity. In contrast to the situation pertaining with the monoquaternary compounds which would seem to be without possible therapeutic application, the short-acting potent non-depolarizing properties of the bisquaternary ammonium compound, coupled with its apparent freedom from undesirable side effects, suggest that serious consideration of clinical trials for this compound is in order.

• Item Type: Thesis (MSc(R))
• Qualification Level: Masters
• Additional Information: Adviser: J J Lewis
• Keywords: Pharmacology
• Date of Award: 1967
• Depositing User: Enlighten Team
• Unique ID: glathesis:1967-72224
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 24 May 2019 15:12
• Last Modified: 24 May 2019 15:12
• URI: https://theses.gla.ac.uk/id/eprint/72224