A new short‐acting non‐depolarizing muscle relaxant (SZ1677) without cardiovascular side‐effects

Abstract

In experiments, SZ1677 proved to be a short-acting neuromuscular blocking compound having a large safety margin between the doses required to produce neuromuscular block and those likely to lead to cardiovascular side-effects.

Development of ultra short‐acting muscle relaxant agents: History, research strategies, and challenges

“…148 Variations of the terminal onium group consisted mainly of applying dialkylamino, piperidino, pyrrolidino, and 1-4 dioxa 8-azaspiro moieties on one side and allyl groups on the other, as was in the case of rocuronium, rapacuronium, 18,148 and SZ 1677. 149,150 As mentioned earlier only partial success was reached with respect to shortening the duration of action with these agents.…”

“…The avenues through which these new agents have been developed followed the trends of: (a) conventional chemical structure and biological activity relationship (SAR) studies and (b) recognized pharmacokineticsprinciples. Regarding the SAR studies performed earlier, and specifically aimed at ultrashort acting agents, the research at Burroughs Wellcome and later Glaxo with large series of tetrahydroisoquinoline-type agents, [135][136][137][138] resulting in GW 280430; 166,169 at Organon NVand Gedeon Richter Co. with numerous amino steroidal NMB agents, 148,149 resulting in rapacuronium and SZ 1677; 150 in Russia with bis adamantane and truxillic acid diesters; 13,180 and in our case with several hundred bis tropinyl diesters, 66,176 leading to TAAC3 (ORG-25-415) 178 should be recognized. Newer approaches included utilization of the recently explored molecular topography of the neuromuscular nicotinic ACh receptor, the site of action of these agents on one hand 37,54,72 and studying the three dimensional aspects of various muscle relaxant molecules 52,183 on the other.…”

Recent Advances in Neuromuscular Blocking Agents

“…SZ-1677 can be derived from rocuronium by a formal substitution of the O-atom in the morpholine ring by the ethylene glycol acetal moiety. The action of 49 on neuromuscular transmission, muscarinic M 2 and M 3 receptors and cardiovascular reactions has been recently examined and its properties compared to those of other aminosteroid muscle relaxants (see Table 5) [55].…”

Effects of SZ1677, a new non‐depolarizing steroidal neuromuscular blocking drug, and rocuronium on two laryngeal muscles and the anterior tibial muscle in guinea pigs

“…The main metabolite of SZ1677 is its 17‐OH derivative SZ1823, which is 27.5 times less potent than SZ1677. In the rat and the guinea pig, the duration of SZ1677 at the anterior tibial muscle did not change with the administration of three repeated ED 90 doses, leading to the conclusion that SZ1677 is without cumulative effect (1). SZ1677 has less of a pre‐synaptic inhibitory effect on acetylcholine release than rocuronium (2).…”

“…SZ1677 [1‐(3α‐hydroxy‐17β‐acetyloxy)‐2β‐(1,4‐dioxa‐8‐azaspiro‐(4.5)dec‐8‐yl)‐(5α‐androstane‐16β‐yl)‐1‐(2‐propenyl)], a pyrrolidinium bromide synthesized by Gedeon Richter Ltd (Budapest, Hungary), is structurally related to rocuronium, at present the only clinically available non‐depolarizing neuromuscular blocking drug with a short onset time. SZ1677 has a rapid onset and a short duration of neuromuscular blockade in various laboratory animal species (1). The main metabolite of SZ1677 is its 17‐OH derivative SZ1823, which is 27.5 times less potent than SZ1677.…”