Twenty-six mono- or bis-quaternary salts of 3,17-dioxy-2 beta, 16 beta-dipiperidino-5 alpha-androstanes (including pancuronium) and one 17-desoxy congener were tested for neuromuscular blocking and autonomic blocking activities in the chloralose-anaesthetized cat. The 17 beta-acetoxy series, all the members of which contain an acetylcholine-like fragment in the steroidal D-ring, was most selective for effecting neuromuscular blockade. The salient member of this series is 3 alpha, 17 beta-diacetoxy-2 beta, 16 beta-dipiperidino-5 alpha-androstane 16 beta-N-monomethobromide (Org NC 45) which is highly selective in blocking neuromuscular transmission in that a dose approximately sixty times greater than the neuromuscular blocking dose was required to block responses to vagal stimulation. In contrast, in doses sufficient to produce neuromuscular block, pancuronium simultaneously blocked responses to vagal stimulation. Moreover, pancuronium and Org NC 45 exhibited the same order of neuromuscular blocking activity and therefore the latter potentially represents a useful addition to the armamentarium of neuromuscular blocking agents currently in clinical use.

The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues, in the cat.

The invention relates to 3α-hydroxy, 17-(un)substituted derivatives of the androstane series and 3α-hydroxy, 21-substituted derivatives of the pregnane series. These derivatives are capable of acting at a recently identified site on the GRC, thereby modulating brain excitability in a manner that will alleviate stress, anxiety, insomnia, mood disorders that are amenable to GRC-active agents (such as depression) and seizure activity. The steroid derivatives of this invention are those having general structural formula (I), wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are further defined herein and the dotted lines are single or double bonds. The structure includes androstanes pregnanes (R4 = methyl), 19-norandrostanes, and norpregnanes (R4 = H).

Neuroactive steroids of the androstane and pregnane series

The introduction of neuromuscular blocking drugs revolutionized the practice of anaesthesia. Before the advent of muscle relaxants, anaesthesia was induced and maintained by intravenous or inhalation agents. Tracheal intubation was uncommon, and muscle relaxation if needed was secured by deep inhalation anaesthesia with its attendant risks of respiratory or cardiac depression. After the introduction of muscle relaxants, anaesthesia underwent a conceptual change. Anaesthesia was redefined as a triad of narcosis, analgesia and muscle relaxation, specific drugs being used to produce each of these effects1.

Muscle relaxants belong to two groups, the depolarizers and the nondepolarizers. Depolarizers mimic the effect of acetylcholine at the neuromuscular junction, first causing muscle contractions (fasciculations) and then paralysing. Suxamethonium, the only depolarizer in use, has the advantage of acting within 60 seconds. Muscle relaxation lasts for under 5 minutes. It is not reversed by anticholinesterases such as neostigmine but plasma cholinesterase causes the effect to wear off quickly. Unwanted effects include malignant hyperpyrexia, increased intraocular pressure and life-threatening hyperkalaemia. Several deaths attributable to hyperkalaemic cardiac arrest have occurred following the use of suxamethonium in children with undiagnosed muscular dystrophies. There is a clinical need for a safer drug that works equally quickly. Nondepolarizers have slower onset (2-3 minutes) and are therefore unsuitable for rapid control of the airway. They work by competitive blockade of the neuromuscular junction and are reversed with anticholinesterases such as neostigmine. There is no initial muscle fasciculation. Important features of some of the nondepolarizers are listed in Table 1.



Table 1

Features of nondepolarizing agents

https://journals.sagepub.com/doi/pdf/10.1177/014107680209500713

Neuromuscular blocking drugs: discovery and development.

Publisher Summary Heterosteroids have recently received much attention. The altered chemical and physical properties are envisaged to lead to the discovery of new substances having the potential of providing some useful drugs. Heterosteroids are divided into nucleo- and extranucleo-categories. The former contain heteroatoms in the nucleus, whereas in the latter, heteroatoms form part of a fused or spiro ring system, an attached group, or a side chain. The facets of heterosteroids discussed in this chapter pertain to adrenocorticoids, anti-mineralocorticoids, anabolics, androgen antagonists and biosynthesis inhibitors, oestrogenic, anti-oestrogenic, progestational, anti-progestational, anti-fertility, catatoxic, cardiac, anti-lipemic, central nervous system acting, neuromuscular blocking, local anaesthetic, diagnostic, antimicrobial, anti-neoplastic, and miscellaneous agents. Medicinal chemists have ventured to modify the corticosteroid structures in different ways and many highly successful drugs have resulted. The chapter focuses on hetero modifications and some closely related aspects. Certain hetero analogues of the mineralocorticoid deoxycorticosterone have been prepared and examined. Some of the synthetic compounds are adrenal inhibitors and anticatabolics.

Heterosteroids and drug research.

The relative potency, time-course of action and cardiovascular effects of Org NC 45, a new non-depolarizing neuromuscular blocking agent, have been compared with those of pancuronium, alcuronium and tubocurarine in 64 anaesthetized patients. The relative potency (ED50) to Org NC 45 was 1.74, 3.69 and 8.57 respectively. In doses which caused useful surgical relaxation, duration of action of Org NC 45 was 34%, 39% and 26% that of pancuronium, alcuroniuym and tubocurarine. After administration of repeated doses no cumulation was seen for Org NC 45. The new drug was free from any effect on arterial pressure and heart rate.

D. S. Savage

Papers

Pancuronium bromide and other steroidal neuromuscular blocking agents containing acetylcholine fragments

Pancuronium bromide and other steroidal neuromuscular blocking agents containing acetylcholine fragments