Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1.

BACKGROUND AND PURPOSE: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. EXPERIMENTAL APPROACH: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. KEY RESULTS: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. CONCLUSIONS AND IMPLICATIONS: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.

On being terminally ill.

In summary, it would seem that the term terminally ill is used to convey an impression that has been formed by the carers, based on actuarial data for the particular disease from which the patient is suffering, their clinical experience dealing with others similarly affected, and a set of traditionally held beliefs. The consequences of describing someone as terminally ill are legion, affecting all aspects of care and involving the belief systems both rational and primitive of carers and patient alike. As long as we understand that it is an opinion, rather than a statement of fact, then the term terminally ill can serve an important function in communicating information in a readily understood form.

Changes in transmission in the pathway of heteronymous spinal recurrent inhibition from soleus to quadriceps motor neurons during movement in man.

H reflexes were induced in the human quadriceps muscle by electrical stimulation of the femoral nerve. The reflexes were conditioned by prior stimulation of the inferior soleus nerve. The conditioning stimulus produced an inhibition of long duration (>20 ms). The threshold of this inhibition was at zero soleus motor discharge and the inhibition scaled with soleus motor discharge. It was concluded that the inhibition was a heteronymous recurrent inhibition of quadriceps motor neurons mediated by Renshaw cells which had been activated by soleus motor neuron discharge. This recurrent inhibition declined during voluntary tonic contraction of the quadriceps, falling to zero at around one-third of maximum voluntary contraction. Antagonist contraction and weak co-contraction of the quadriceps and its antagonists did not lead to any significant change in recurrent inhibition. It is concluded that motor commands descending from the brain reduce heteronymous recurrent inhibition during isolated quadriceps muscle contraction, but to a much lesser extent during co-contraction. No evidence was obtained for any descending facilitation of heteronymous recurrent inhibition.

Task-related changes of transmission in the pathway of heteronymous spinal recurrent inhibition from soleus to quadriceps motor neurones in man.

An H reflex conditioning technique was used to monitor the transmission of heteronymous recurrent inhibition from soleus to quadriceps motor neurones of the human lower limb. Inhibition declined during quadriceps muscle contraction under all conditions examined, falling to zero at around one-third of the maximum voluntary contraction. Inhibition declined during soleus muscle contraction in sitting, standing and bicycling tasks. The level of inhibition assessed at a given (weaker than 30%) level of quadriceps contraction was reduced during postural tasks involving quadriceps and soleus co-contraction (standing and late-stance phase of walking) when compared with sitting and performing matched voluntary muscle contractions. The level of inhibition during the mid-power stroke of a bicycling task, which also involved co-contraction of quadriceps and soleus, was greater than during matched voluntary muscle contractions while sitting. It is concluded that the pathway of heteronymous recurrent inhibition from soleus to quadriceps motor neurones is under at least two types of control: one related to the task, which sets the operating range, and a second which couples inhibition to the level of muscle contraction. Multiple control pathways are consistent with the diverse effects on recurrent inhibition reported in subjects with upper motor neurone lesions.