Ann Gail Hayes

Determination of receptors that mediate opiate side effects in the mouse

1 The effects of μ and κ‐opiate receptor agonists were studied in a variety of tests in the mouse designed to correspond to clinical side‐effects in man. These included sedation, decrease in pupil diameter, Straub tail, decrease in body temperature, decrease in respiratory rate and inhibition of gut propulsion. 2 The μ‐receptor agonists tested produced opiate side‐effects in the mouse at doses between 2.4 and 34 times higher than their antinociceptive doses in the abdominal constriction test. Their ranked orders of potency in producing these effects were very similar to their order of antinociceptive potency. 3 In contrast, the κ‐receptor agonists only produced opiate side‐effects at doses between 29 and >2500 times higher than their antinociceptive doses. There was no correlation between the potency ratios in these tests and in the abdominal constriction test. 4 It is concluded that μ‐receptor agonists may produce both their antinociceptive effects and opiate side‐effects by interacting with the μ‐receptor. The κ‐receptor agonists have previously been shown to produce antinociception via the κ‐receptor, but the opiate‐like side‐effects which appear with some of the drugs at much higher doses are probably due either to interaction with the μ‐receptor or to some other non‐specific action.

Effects of single doses of capsaicin on nociceptive thresholds in the rodent

Abstract The aim of the present investigation was to determine the acute effects of single doses of capsaicin, administered either peripherally or centrally, against responses induced by chemical, heat and pressure nociceptive stimuli in the rat and mouse. In the mouse, subcutaneous capsaicin treatment produced a significant decrease in the number of abdominal constriction responses produced by intraperitoneal injections of either acetylcholine or phenylquinone. Hot plate studies in the same mice showed that capsaicin was ineffective against thermal nociceptive stimuli at doses 20 times greater than those effective against chemical nociceptive stimuli. In the rat, subcutaneous administration of capsaicin caused a dose-related antinociceptive effect against a chemical nociceptive stimulus, using the formalin test. Nociceptive pressure thresholds determined for both hind paws were significantly higher in rats receiving capsaicin either subcutaneously, intracerebroventricularly or intrathecally. In marked contrast, nociceptive heat thresholds were unchanged in rats treated with capsaicin either peripherally or centrally. No gross behavioral changes were observed in the capsaicin treated animals. In conclusion, these results show that single doses of capsaicin administered either peripherally or centrally, caused short-lasting increases in pressure and chemically-induced nociception, whilst nociceptive heat thresholds were unaffected.

Pharmacology of δ-opioid receptor in the hamster vas deferens

Abstract Electrically evoked contractions of the hamster isolated vas deferens are inhibited only by opiod drugs which have agonist activity at δ-opioids receptors. Opioid which are μ-, κ- or σ-selective were either inactive or were antagonists. The compound β-funaltrexamine, which irreversibly blocks μ- and δ-opioid receptors, caused a flattening of the dose-response curve and a reduced maximum inhibition available to δ-opioid agonists. Analysis of the curves by the double-reciprocal null method enable the affinity of these agonists at δ-opioid receptors to be calculated.

EFFECTS OF γ‐AMINOBUTYRIC ACID ON NERVE TERMINAL EXCITABILITY IN A SLICE PREPARATION OF CUNEATE NUCLEUS

1 Superfusion of a slice preparation of the rat cuneate nucleus with γ‐aminobutyric acid (GABA) depolarized the afferent nerve fibres and increased their excitability. However, before the depolarization had reached its peak the increased excitability reversed to a decreased excitability, an effect which outlasted the depolarization. 2 Both components of the GABA excitability response were dose‐related, CI “‐dependent and antagonized by bicuculline. 3 Possible mechanisms underlying the sequence of excitability changes are discussed.

Effect of four convulsants on the time course of presynaptic inhibition and its relation to seizure activity

Abstract The effects of bicuculline, picrotoxin, leptazol and bemegride on presynaptic inhibition were studied in the rat cuneate nucleus, using the excitability testing technique to measure the depolarization of the primary afferent terminals (PAD). Depolarization of primary afferent terminals was represented by the increase in excitability of cuneate presynaptic terminals produced by conditioning volleys from the median nerve (applied 10–70 msec before the test volley). None of the convulsants had any effect on resting terminal excitability, but bicuculline reduced the increase in excitability obtained with conditioning-test intervals of 10–30 msec, and picrotoxin, leptazol and bemegride reduced it over all the intervals tested. The reduction in PAD occurred simultaneously with the first signs of convulsant effects in the electrocorticogram.

Why is publication of negative clinical trial data important

The pharmaceutical industry is facing troubled times, both in the UK and globally. Revenues are being hit by patent expiries on blockbuster drugs like atorvastatin, salmeterol xinafoate/fluticasone propionate and olanzapine; and development pipelines are insufficiently robust to replace these lost revenues. Drug discovery productivity has failed to improve over the last 15 years, despite the large sums of money that have been spent on research and development (RD Pangalos et al., 2007) although phase III failure rates in CNS are lower than those in oncology (Arrowsmith, 2011a). This has resulted in several large companies scaling down their research operations (GlaxoSmithKline in the UK and Verona, Merck in the UK, Pfizer in the UK at Sandwich, Novartis in Switzerland and AstraZeneca at Loughborough in the UK) in an effort to reduce costs and refocus research on areas seen to be less risky. Such closures can have a direct effect on the regional economy in these areas and also an impact on national academic research as there are fewer opportunities for collaboration and for leveraging industry funding. Various solutions have been implemented with a view to improving productivity: research operations are being split into smaller units in an effort to recapitulate the innovative culture of the small biotechnology companies, such as the GSK CEDDs (Centres of Excellence for Drug Discovery) and DPUs (Discovery Performance Units) and Pfizers NewMeds business units; pipelines are being replenished from small and larger biotechnology companies through a range of different deal types; and contract research is being sourced in Asia where costs are currently lower. However, there is no clear indication that such changes will increase the probability of success, although they may reduce the cost of failure. Clearly, methods of reducing attrition should be pursued at all points along the drug discovery and development process. However, the impact of reducing failure in clinical trials should be greater than reducing failure in the discovery phase, as this is where the most spend occurs.

Synthesis, antinociceptive activity and opioid receptor profiles of trans-3-(octahydro-2H-pyrano[2,3-c]pyridin-4a-yl)phenols and trans-3-(octahydro-1H-pyrano[3,4-c]pyridin-4a-yl)phenols

The synthesis of a series of novel trans-3-(octahydro-2H-pyrano[2,3-c]pyridin-4a-yl)phenols (12a–g), (20a–c), (21), (22) and trans-3-(octahydro-1H-pyrano[3,4-c]pyridin-4a-yl) phenols (28a, b), (34) is described. Construction of the pyrano[2,3-c]pyridines is achieved via annulation of the pyran ring onto the arylpiperidin-3-ones (6) and (14)(R = CO2Ph). The pyrano[3,4-c]pyridines are synthesized by application of metallated enamine chemistry to 1-methyl-4-(3-methoxyphenyl)1,2,3,6-tetrahydropyridine (4) and proceeds via the novel 2-oxa-8-azabicyclo[3.3.1 ] nonane (23) and the bicyclic enamines (24) and (29). Manipulation of this general methodology has afforded a number of structural variants bearing strategic substitutions in the pyran ring as well as alternative N-groups. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure-activity relationships are discussed.

Synthesis, antinociceptive activity, and opioid receptor profiles of 10-substituted-6-oxamorphinans

A concise synthesis of the 6-oxamorphinan ring system has been designed which allows introduction of functionality at the 10-position. This has provided a series of 10-methylene-, 10-oxo-, and 10α-methyl-6-oxamorphinans, (24a–e), (25a–d), and (26a–c) respectively. The enamine 8a-(3-methoxyphenyl)-6-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrano[4,3-c]pyridine (4a) is converted in three steps, via trans-8a-(3-methoxyphenyl)-6-methyloctahydropyrano[4,3-c]pyridine-5α-carbonitrile (7a) and the corresponding 5α-acetyl derivative (9a), to the tetracyclic 10-methylene-6-oxamorphinan (11a). Oxidative cleavage of the 10-exocyclic methylene group of (11a) provides entry into the 10-oxo series. The antinociceptive activity and opioid receptor profiles of (24a–e), (25a–d), and (26a–c) have been evaluated and structure–activity relationships are discussed.

Synthesis, antinociceptive activity and opioid receptor profiles of 3-(octahydro-1H-pyrano- and -thiopyrano[4,3-c]pyridin-8a-yl)phenols

The synthesis of a series of novel cis- and trans-3-(octahydro-1H-pyrano[4,3-c]pyridin-8a-yl)phenols (13a–1), (15a, b), (20a–d), (21a–e) and the trans-3-(octahydro-1H-thiopyrano[4,3-c]pyridin-8a-yl)phenol (26) is described. Alkylation of 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (7) with 2-chloro-1-(chloromethoxy)ethane or 2-chloro-1-(chloromethoxy)propane, and subsequent cyclization, generated the bicyclic enamines (9a) and (9b) respectively. Hydrogenation of (9a, b) under neutral conditions provided the trans-fused octahydropyrano[4,3-c]pyridines (10a), (16a), and (17a), whereas hydrogenation of (9a) in acidic media gave the corresponding cis-fused system (11a). The trans-fused octahydrothiopyrano[4,3-c]pyridine (23) was synthesized via the analogous enamine (22). Selected N-substituents were introduced via a vinyl chloroformate N-demethylation/re-alkylation sequence and subsequent O-demethylation afforded the title phenols. The antinociceptive activity and opioid receptor profile of these compounds has been determined and structure activity relationships are discussed.