Replies to post #15077 on RespireRx Pharmaceuticals Inc (RSPI)

[enemem]

It seems to me that this drug may at least mitigate the RD associated with opiates. Below is the abstract of the following ms:
Norepinephrine differentially modulates different types of respiratory pacemaker and nonpacemaker neurons.
Viemari JC, Ramirez JM.

Pacemakers are found throughout the mammalian CNS. Yet, it remains largely unknown how these neurons contribute to network activity. Here we show that for the respiratory network isolated in transverse slices of mice, different functions can be assigned to different types of pacemakers and nonpacemakers. This difference becomes evident in response to norepinephrine (NE). Although NE depolarized 88% of synaptically isolated inspiratory neurons, this neuromodulator had differential effects on different neuron types. NE increased in cadmium-insensitive pacemakers burst frequency, not burst area and duration, and it increased in cadmium-sensitive pacemakers burst duration and area, but not frequency. NE also differentially modulated nonpacemakers. Two types of nonpacemakers were identified: "silent nonpacemakers" stop spiking, whereas "active nonpacemakers" spontaneously spike when isolated from the network. NE selectively induced cadmium-sensitive pacemaker properties in active, but not silent, nonpacemakers. Flufenamic acid (FFA), a blocker of ICAN, blocked the induction as well as modulation of cadmium-sensitive pacemaker activity, and blocked at the network level the NE-induced increase in burst area and duration of inspiratory network activity; the frequency modulation (FM) was unaffected. We therefore propose that modulation of cadmium-sensitive pacemaker activity contributes at the network level to changes in burst shape, not frequency. Riluzole blocked the FM of isolated cadmium-insensitive pacemakers. In the presence of riluzole, NE caused disorganized network activity, suggesting that cadmium-insensitive pacemakers are critical for rhythm generation. We conclude that different types of nonpacemaker and pacemaker neurons differentially control different aspects of the respiratory rhythm.

This in vitro study shows that NE overall increased drive from pacemakers in the PreBotC, and increased their number. Insofar as pacemakers are causal to respiratory rhythm generation, increasing their activity would seem to increase respiratory drive, which should counteract the the depressive effects of opioids. These in vitro data need to be taken with a pinch of salt, because it's not always the case that respiratory network behavior in vivo responds in the same way to pharmacological manipulations as the highly reduced preparation used here, but it looks to me like this drug should reduce the risk of RD while maintaining analgesia.

[enemem]

I went to the Abstract where this compound is described:

-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.
Tzschentke TM, Christoph T, Kögel B, Schiene K, Hennies HH, Englberger W, Haurand M, Jahnel U, Cremers TI, Friderichs E, De Vry J.



ABSTRACT
(
)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol
hydrochloride (tapentadol HCl) is a novel
-opioid receptor
(MOR) agonist (Ki  0.1
M; relative efficacy compared with
morphine 88% in a [35S]guanosine 5-3-O-(thio)triphosphate
binding assay) and NE reuptake inhibitor (Ki  0.5
M for
synaptosomal reuptake inhibition). In vivo intracerebral microdialysis
showed that tapentadol, in contrast to morphine, produces
large increases in extracellular levels of NE (450% at
10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide
range of animal models of acute and chronic pain [hot plate,
tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic
constriction injury (CCI), and spinal nerve ligation (SNL)], with
ED50 values ranging from 8.2 to 13 mg/kg after i.p. administration
in rats. Despite a 50-fold lower binding affinity to MOR, the
analgesic potency of tapentadol was only two to three times
lower than that of morphine, suggesting that the dual mode of
action of tapentadol may result in an opiate-sparing effect. A
role of NE in the analgesic efficacy of tapentadol was directly
demonstrated in the SNL model, where the analgesic effect of
tapentadol was strongly reduced by the 2-adrenoceptor antagonist
yohimbine but only moderately attenuated by the MOR
antagonist naloxone, whereas the opposite was seen for morphine.
Tolerance development to the analgesic effect of tapentadol
in the CCI model was twice as slow as that of morphine.
It is suggested that the broad analgesic profile of tapentadol
and its relative resistance to tolerance development may be
due to a dual mode of action consisting of both MOR activation
and NE reuptake inhibition.

This abstract suggests that the risk of RD is attenuated because much of the analgesic effect is mediated by NE receptor activation, which is corroborated by the slower rate of tolerance development.

My hope is that this compound will at best claim the chronic pain management market, without affecting cor's prospects in post-operative RD. Still for me it is a real wake-up call, in that I hadn't considered the possibility that cor might get scooped. Certainly, if this drug is approved for chronic use, the manufacturer shouldn't have too hard a time expanding its use to the post-operative arena.