Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters.

A series of benzene ring substituted ketamine N-alkyl esters were prepared from the corresponding substituted norketamines. Few of the latter have been reported since they have not been generally accessible via known routes. We report a new general route to many of these norketamines via the Neber (oxime to α-aminoketone) rearrangement of readily available substituted 2-phenycyclohexanones. We explored the use of the substituents Cl, Me, OMe, CF3, and OCF3, with a wide range of lipophilic and electronic properties, at all available benzene ring positions. The 2- and 3-substituted compounds were generally more active than 4-substituted compounds. The most generally acceptable substituent was Cl, while the powerful electron-withdrawing substituents CF3 and OCF3 provided fewer effective analogues.

Ketamine esters and amides as short-acting anaesthetics: Structure-activity relationships for the side-chain.

N-Aliphatic ester analogues of the non-opioid ketamine (1) retain effective anaesthetic/analgesic properties while minimising ketamine's psychomimetic side-effects. We show that the anaesthetic/analgesic properties of these ester analogues depend critically on the length (from 2 to 4 carbons), polarity and steric cross-section of the aliphatic linker chain. More stable amide and ethylsulfone analogues generally showed weaker anaesthetic/analgesic activity. There was no correlation between the anaesthetic/analgesic properties of the compounds and their binding affinities for the N-methyl-d-aspartate (NMDA) receptor.

NNZ-2566: a Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke.

The N-terminal cleavage product of human insulin-like growth factor-1 (IGF-1) in the brain is the tripeptide molecule Glypromate (Gly-Pro-Glu). Glypromate has demonstrated neuroprotective effects in numerous in vitro and in vivo models of brain injury and is in clinical trials for the prevention of cognitive impairment following cardiac surgery. NNZ-2566 is a structural analogue of Glypromate, resulting from alpha-methylation of the proline moiety, which has improved the elimination half-life and oral bioavailability over the parent peptide. In vivo, NNZ-2566 reduces injury size in rats subjected to focal stroke. An intravenous infusion of NNZ-2566 of 4 h duration (3-10 mg/kg/h), initiated 3 h after endothelin-induced middle-cerebral artery constriction, significantly reduced infarct area as assessed on day 5. Neuroprotective efficacy in the MCAO model was also observed following oral administration of the drug (30-60 mg/kg), when formulated as a microemulsion. In vitro, NNZ-2566 significantly attenuates apoptotic cell death in primary striatal cultures, suggesting attenuation of apoptosis is one mechanism of action underlying its neuroprotective effects. NNZ-2566 is currently in clinical trials for the treatment of cognitive deficits following traumatic brain injury, and these data further support the development of the drug as a neuroprotective agent for acute brain injury.

Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.

5-HT2C receptor agonists as potential drugs for the treatment of obesity.

An association between the brain serotonin (5-HT) system and feeding has been postulated since the 1970's but it has only been in recent years that the nature of 5-HT-mediated hypophagia has become well understood, and the receptor subtypes responsible for the effect better defined. The invention and utilisation of subtype-selective 5-HT receptor antagonists has demonstrated that the 5-HT(2C) receptor is of paramount importance in this regard. Importantly, ethological studies of animal behaviour have shown that the hypophagia resulting from 5-HT(2C) receptor activation is likely to be a consequence of increased satiety and this is in contrast to hypophagia following 5-HT(2A) receptor activation. Furthermore, recent studies have also shown that 5-HT(2C) receptor agonists not only reduce feeding when acutely administered to rats or mice, they can also reduce body weight without inducing tolerance when administered chronically to obese animals. These observations have led researchers to conclude that selective 5-HT(2C) receptor agonists have the potential to be effective anti-obesity agents. Encouragingly, this suggestion is supported by both direct and indirect evidence from clinical studies. Indirect evidence stems from recent observations that the clinically effective anorectic agent d-fenfluramine exerts its hypophagic and weight-loss effects via 5-HT(2C) receptor activation. More direct clinical evidence derives from the use of the prototypical 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP), with which both acute hypophagia and body-weight loss have been observed. The current paper therefore reviews both the pre-clinical and clinical evidence supporting the use of 5-HT(2C) receptor agonists for the treatment of obesity and assesses the developments that have been made in this regard to date.