Neuromuscular Blocking Properties of Stereoisomeric Androstane‐3, 17‐bisquaternary Ammonium Salts

Bamford, D. G.; Biggs, David F.; Davis, M.; Parnell, E. W.

doi:10.1111/j.1476-5381.1967.tb02125.x

Cited by 21 publications

(8 citation statements)

References 17 publications

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“…A naturally occurring steroidal alkaloid, malouetine (3,8,20,8-bis dimethylamino-5a-pregnane bismethochloride) and its steroisomers (Khuong Huu-Laine & Pinto-Scognamiglio, 1964) possess similar potency to tubocurarine but produce hypotension when injected. Recently, Alauddin, Caddy, Lewis, Martin-Smith & Sugrue (1965) and Bamford, Biggs, Davis & Parnell (1967) synthesized and tested stereoisomers of dialkylaminoand cyclic amino-steroids substituted at positions 3 and 17; they all possessed lower potency than tubocurarine in cat or monkey. In pancuronium, the acetyl groups present at positions 3 and 17 adjacent to the 2,16 amino functions could afford some steric compression in rings A and D of the steroid molecule, so that ring-A is held in an intermediate skew position between the possible rigid configurations (boat or chair), which might be optimal for association with a receptor site, and thus contribute to the high potency obtained.…”

Section: Acute Toxicitymentioning

confidence: 99%

The Pharmacology of Pancuronium Bromide (ORG.NA97), a New Potent Steroidal Neuromuscular Blocking Agent

Buckett¹,

Marjoribanks²,

Marwick³

et al. 1968

British Journal of Pharmacology and Chemotherapy

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The incorporation of a biologically active group into a naturally occurring structure is an interesting approach to new pharmacological agents. For example, when an acetylcholine-like structure is incorporated in ring-A of 5a-androstane-17-one or 5a-pregnan-20-one, neuromuscular blocking agents of up to one-fifteenth the potency of tubocurarine are obtained (Lewis, Martin-Smith, Muir & Ross, 1967). Although of limited clinical value, such compounds present useful leads for further chemical exploration, particularly the synthesis of bisquaternary amino-steroidal salts. A series of 2,8,16,3-diamino-5a-androstane-3a,17p-diol dimethohalide derivatives was described by Buckett, Hewett & Savage (1967). One of them, 2ft,16,/-dipiperidino-5a-androstane3a,17,8-diol diacetate dimethobromide (code number Org.NA97; approved name pancuronium bromide), is a potent neuromuscular blocking agent and in the experiments described in this paper its actions were compared with those of tubocurarine chloride. Cats were anaesthetized with a mixture of chloralose (70 mg/kg) and sodium pentobarbitone (12 mg/kg) injected intraperitoneally; rabbits and dogs were anaesthetized with sodium pentobarbitone (45 mg/kg) injected intravenously, and hens with sodium barbitone (200 mg/kg) injected intravenously. In all species the trachea was intubated and artificial ventilation applied throughout each experiment Twitches and tetani of a gastrocnemius muscle were elicited by stimulating the peripheral portion of the crushed sciatic nerve in the popliteal space with rectangular shocks of

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Section: Acute Toxicitymentioning

confidence: 99%

The Pharmacology of Pancuronium Bromide (ORG.NA97), a New Potent Steroidal Neuromuscular Blocking Agent

Buckett¹,

Marjoribanks²,

Marwick³

et al. 1968

British Journal of Pharmacology and Chemotherapy

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“…Stenlake (1963) has drawn attention to the rigidity of the steroid nucleus in relation to biological activity, and Alauddin et al (1965) investigated their series of bis-quaternary androstane compounds specifically because of the relatively inflexible configuration of the nucleus. Alauddin et al (1965) concluded that a " fixed" interonium distance was relatively unimportant in determining neuromuscular blocking activity, a conclusion also reached by Bamford et al (1967) who investigated a series of stereoisomeric androstane 3,17-bisquaternary salts. Bamford et at.…”

Section: Discussionmentioning

confidence: 87%

“…Alauddin et al (1965) concluded that a " fixed" interonium distance was relatively unimportant in determining neuromuscular blocking activity, a conclusion also reached by Bamford et al (1967) who investigated a series of stereoisomeric androstane 3,17-bisquaternary salts. Bamford et at. (1967) have suggested that the configuration of the quaternary centres, and the shape and nature of the structure joining them, are at least as important as interonium distance in determining potency.…”

Section: Discussionmentioning

confidence: 87%

NEUROMUSCULAR BLOCKING ACTIVITIES OF SOME STEROIDAL MONO AND BIS‐QUATERNARY AMMONIUM COMPOUNDS WITH SPECIAL REFERENCE TO NN'‐DIMETHYLCONESSINE

Busfield¹,

Child²,

Clarke³

et al. 1968

British Journal of Pharmacology and Chemotherapy

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The pharmacological properties of conessine, 3-/3-dimethylamino-con-5-ene, a steroidal alkaloid obtained from the bark and seeds of Holarrhena antidysenterica have been described (Burn, 1914;Stephenson, 1948). Quaternary salts of the alkaloid have been prepared (Polstorff & Schirmer, 1886;Bertho, 1944) but do not seem to have been examined pharmacologically. We report here the results of an investigation of structureactivity relationships in a series of quaternary ammonium compounds derived from conessine or related steroids which possess neuromuscular blocking properties of the non-depolarizing type. The results for one compound, NN'-dimethylconessine, which is typical of this group and has been submitted for clinical trial, are recorded in detail. METHODS CatsAdult cats of either sex were anaesthetized by intraperitoneal injection of chloralose (80 mg/kg) with pentobarbitone sodium (10 mg/kg). The right hind limb was set up in the horizontal position on a Brown-Schuster myography stand. The sciatic nerve was ligated, cut centrally and stimulated peripherally using shielded silver electrodes. Twitches and tetani were elicited in the tibialis anterior and soleus muscles by square wave pulses of 0.2 msec duration and of twice the strength required to produce maximal twitches of the muscles. The muscles were attached to flat steel springs and the contractions recorded semi-isometrically on a smoked paper. The muscles were warmed with a lamp and kept moist with liquid paraffin saturated with physiological saline. In some experiments, stimuli of supramaximal strength and 0.5 msec duration were applied directly to the tibialis anterior muscle between the tendon and the drill in the femur, using shielded silver wire. Close-arterial injections were made to the tibialis anterior muscle as described by Brown (1938). Gross muscle action-potentials were recorded on a Tektronix 502 dual-beam oscilloscope from platinum electrodes inserted through the belly and tendon of the tibialis muscle, and the antidromic nerve action potentials were recorded from shielded platinum electrodes placed on the sciatic nerve. Drugs were injected into the right external jugular vein through a tap cannula, and the left carotid arterial pressure was recorded using a mercury manometer. Artificial respiration was applied through-a. tracheal cannula connected to a Palmer respiration pump.

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“…There is little doubt that the paper by Khuong-Huu-Laine Â and PintoScognamiglio confirming the neuromuscular blocking activity of malouetine and its stereo-isomers [24] induced continued support for the search for a superior aminosteroid muscle relaxant. In 1967, the May and Baker group freely admitted [25] that it had been prompted to synthesise dipyrandium and derivatives by the discovery (Quevauviller and Laine Â, 1960) of the curarising properties of malouetine.…”

mentioning

confidence: 99%

Prelude to pancuronium and vecuronium

McKenzie

2000

Anaesthesia

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SummaryThe discovery of the neuromuscular blocking activity of malouetine isolated from Malouetia bequaertiana Woodson by Quevauviller and Laine Â in 1960 stimulated interest in aminosteroids as potential neuromuscular blockers. Alauddin (a pharmacist) and Martin-Smith (a medicinal chemist) began research in this area, which was then taken up by pharmaceutical companies. Pure pancuronium was synthesised in 1964 by Savage and his co-workers, directed by Hewett. Pharmacologists headed by Buckett discovered that pancuronium was far more potent than dtubocurarine and had minimal side-effects. Buckett quickly recognised the value of pancuronium, and his persistence resulted in successful clinical trials, followed by the commercial launch of pancuronium in 1968. Vecuronium was synthesised, tested and the studies published by Buckett, Hewett and Savage in 1973, but this was before anaesthetists called for a`clean muscle relaxant' and, furthermore, it was unstable in aqueous solution. Hence, it was only promoted for clinical trials six years later.

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Neuromuscular Blocking Properties of Stereoisomeric Androstane‐3, 17‐bisquaternary Ammonium Salts

Cited by 21 publications

References 17 publications

The Pharmacology of Pancuronium Bromide (ORG.NA97), a New Potent Steroidal Neuromuscular Blocking Agent

The Pharmacology of Pancuronium Bromide (ORG.NA97), a New Potent Steroidal Neuromuscular Blocking Agent

NEUROMUSCULAR BLOCKING ACTIVITIES OF SOME STEROIDAL MONO AND BIS‐QUATERNARY AMMONIUM COMPOUNDS WITH SPECIAL REFERENCE TO NN'‐DIMETHYLCONESSINE

Prelude to pancuronium and vecuronium

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