Analogs of thyrotropin-releasing hormone: Hypotheses relating receptor binding to net excitation of spinal lower motor neurons

Pharmacological and biochemical comparison of thyrotropin releasing hormone (TRH) and di‐methyl proline‐TRH on pituitary GH3 cells

“…The likelihood of two sites is not supported by the similarities of the Hill coefficients for the two ligands. The affinity of RX77368 was nine times lower than that of the parent compound, the latter agreeing well with results obtained by Hawkins et al (1986) and Sharif et al (1989) for the inhibition of [3H]-methyl-TRH binding to spinal cord and brain membrane preparations. There was an excellent correlation between the rank order of potency of various analogues to inhibit [3H]-TRH or [3H]-RX77368 binding, strongly suggesting that RX77368 binds to the GH3 cell TRH receptor.…”

“…The latter has been attributed to the greater metabolic stability hence increased bioavailability of the analogue; however, other factors, for example active metabolites or enhanced potency at the receptor, may play a role. While there are no known active metabolites of RX77368, indeed much of a dose is excreted unchanged , there has to date been no data published concerning the direct binding characteristics of the drug, although Hawkins et al (1986) and more recently Sharif et al (1989) have shown indirectly that RX77368 has a lower affinity than TRH for mammalian spinal cord and brain receptors. Here we have had the unique opportunity of investigating the binding characteristics of tritiated RX77368 and comparing them to those of the parent compound in whole GH3 pituitary cells, a clonal cell line having receptors for TRH that are coupled to phosphoinositide (PI) hydrolysis and prolactin release (Tashjian et al, 1971;Drummond & Macphee, 1981;Sutton & Martin, 1982).…”

Clinical Pharmacology of Motor Neurons

“…DN1417, an analogue with low affinity for spinal cord TRH receptors, produces a similar but delayed and more marked effect on EMG activity. It was suggested that TRH-induced lower motor neuron excitation is mediated by non-TRH receptors (Barbeau and B6dard 1981;Hawkins and Enge11985;Hawkins et al 1986). In rat cerebral cortex the effects of TRH have been less consistent; both potentiation of the excitatory action of acetylcholine and lack of it, have been reported (Yarbrough 1976;Winokur and Beckman 1978).…”

Lack of Usefulness of DN‐1417 for Characterization of a CNS Receptor for Thyrotropin‐Releasing Hormone

“…Experimentally, we and others have demonstrated a neurotransmitter-like net excitation of spinal lower motor neurons (LMNs) by thyrotropin-releasing hormone (TRH) (summarized in Hawkins et al, 1986) that parallels the clinical use of the peptide for the symptomatic relief of weakness in amyotrophic lateral sclerosis and other motor neuron disorders (Engel et al, 1983(Engel et al, , 1984aSufit et al, 1984). Clinically, infusion of the drug causes a reduction in or complete loss of the excitatory response, an effect operationally termed "autorefractoriness" (AR) (Engel and Sid-dique, 1984).…”