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Biomedical subjects

A Naylor

Publications and source records attributed to A Naylor.

At least 19 recordsLinked to original sources
PubMed1994

4-[(Alkylamino)methyl]furo[3,2-c]pyridines: a new series of selective kappa-receptor agonists.

The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-pyrrolidinol analogue 17 (IC50 = 2.7 nM) was found to be approximately 5-fold more potent than the corresponding pyrrolidine analogue 16 (IC50 = 15 nM). In the rat and hamster vasa deferentia (mu-specific and delta-specific tissues, respectively), 17 showed only weak antagonist activity (pKB > 5.5), underlining its selectivity for the kappa-opioid receptor. The major activity for 17 is resident in the 4S,3'S-isomer 26 (rabbit vas deferens IC50 = 1.1 nM). Compound 26 displays excellent antinociceptive activity, as determined in the mouse acetylcholine-induced abdominal constriction test (ED50 = 0.001 mg/kg, sc).

Analgesics↗
PubMed1993

A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines (10-22, 26, 27, and 30-33) and their activities as kappa-opioid receptor agonists are described. This includes a range of 4-acyl and 4-carboalkoxy derivatives with the latter series showing the greatest kappa-agonist activity. In particular, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate (18) displays exceptional potency and selectivity. It showed the following activities in functional in vitro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 nM, rat vas deferens (mu-specific tissue) IC50 > 10,000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10,000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mouse acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 mg/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. The kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this region of the molecule is an important requirement for optimal potency.

Analgesics↗
PubMed1992

New kappa-receptor agonists based upon a 2-[(alkylamino)methyl]piperidine nucleus.

The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]- 2-[[1-(3-oxopyrrolidinyl)]methyl]piperidine (10) possesses high activity in the rabbit vas deferens (LVD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc). The spirocyclic analogue 8-[(3,4-dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dio xa-8- azaspirol4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.

Analgesics↗
PubMed1992

GR94839, a kappa-opioid agonist with limited access to the central nervous system, has antinociceptive activity.

1. The pharmacological profile of GR94839, a kappa-opioid agonist with limited access to the central nervous system, has been investigated. Its antinociceptive activity has been compared with that of GR103545, a centrally-penetrating kappa-agonist and ICI204448, the previously described peripherally-selective kappa-agonist. 2. GR94839 was a potent agonist in the rabbit vas deferens in vitro assay for kappa-opioid receptors (IC50: 1.4 +/- 0.3 nM; n = 6), but had limited activity at mu- or delta-opioid receptors. 3. In the mouse abdominal constriction test, GR94839 was 238 fold more potent when given i.c.v. (ED50: 0.008 (0.004-0.029) mg kg-1; n = 18) than when s.c. (ED50: 1.9 (0.7-3.1) mg kg-1; n = 30). In comparison, GR103545 was equipotent when given i.c.v. or s.c. 4. After intravenous administration, the maximum plasma to brain concentration-ratio attained by GR94839 was 18 compared with 2 for GR85571, a structurally-related kappa-agonist that is centrally-penetrating. 5. GR94839 inhibited the 2nd phase of the rat formalin response at doses 7 fold lower than those required to inhibit the 1st phase (ED50 vs 1st phase: 10.2 (6.7-17.1) mg kg-1, s.c.; ED50 vs 2nd phase: 1.4 (1.0-1.8) mg kg-1, s.c.; n = 18). GR103545 was equipotent against the two phases. 6. Intraplantar administration of the opioid antagonists, norbinaltorphimine (100 micrograms) or naltrexone (1 microgram), reversed the antinociceptive effect of systemic GR94839 (3 mg kg-1, s.c.) against the 2nd phase of the formalin response and intraplantar injection of GR94839 (30-100 micrograms) selectively inhibited the 2nd phase.7. GR94839 and IC1204448 reversed the hyperalgesia in the zymosan-inflamed rat paw at doses (ED50 GR94839: 2.0 (1.1-3.2) mg kg-', s.c.; ED50 IC1204448: 1.2 (0.8-1.7) mg kg-', s.c.), lower than those required to raise the noxious pressure threshold in the non-inflamed paw (EDSO GR94839: 16.4 (8.6-46.7) mg kg', s.c.; ED50 IC1204448: 68.0 (22.1-32000) mg kg', s.c.). GR103545 raised the noxious presure threshold in the inflamed and non-inflamed paws at the same doses.8. GR94839 was sedative in the rat rotarod test (ED50: 35 (12-245) mg kg-', s.c.) at doses higher than those required to inhibit the 2nd phase of the formalin response or reverse hyperalgesia in the zymosan-inflamed rat paw. The doses were comparable to those that inhibited the 1st phase of the formalin response and raised the noxious pressure threshold in the non-inflamed paw.9. The results suggest that GR94839 is a selective kappa-agonist which has antinociceptive activity against inflammatory pain at doses that produce limited central effects. These antinociceptive effects are probably mediated at peripheral opioid receptors.

Analgesics↗
PubMed1991

Neuroprotective actions of GR89696, a highly potent and selective kappa-opioid receptor agonist.

1. The effect of a novel, highly potent and selective kappa-opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2. In the Mongolian gerbil model, administration of GR89696 (3 to 30 micrograms kg-1, s.c.), immediately before and at 4 h after insult, produced a dose-dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7-min bilateral carotid occlusion. Similar effects were obtained with two other kappa-agonists, GR86014 (1 mgkg-1, s.c.) and GR91272 (1 mgkg-1, s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mgkg-1, s.c. Repeated post-treatment with GR89696 (100 micrograms kg-1, s.c.) or GR44821 (10 mgkg-1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia-induced neurodegeneration. 3. In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 micrograms kg-1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 micrograms kg-1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4. The results indicate that the potent kappa-opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention.

Animals↗
PubMed1990

A series of novel, highly potent and selective agonists for the kappa-opioid receptor.

1. This paper describes the opioid receptor pharmacology and in vivo activity of several novel benzene-acetamidopiperidine and benzeneacetamidopiperazine analogues. 2. These compounds all showed potent, naloxone-reversible, full agonist activity in the field-stimulated rabbit vas deferens, indicating that they are kappa-opioid agonists; but showed very little activity in the rat or hamster vas deferens, indicating good selectivity with regard to mu- and delta-opioid receptors. 3. They were all potent antinociceptive agents, the most potent compound, GR 103545, having an ED50 value in the mouse abdominal constriction test of 0.25 micrograms kg-1 s.c. The compounds also produced sedation and diuresis, but had little effect on respiration rate or gastrointestinal motility. 4. It is concluded that the seven novel compounds described are all potent and selective agonists for the kappa-opioid receptor.

Abdomen↗
PubMed1990

Professional education and training for trainers.

There is a worldwide need for health professionals knowledgeable in lactation physiology and breastfeeding management. The seven step Wellstart education program is aimed at physician-nurse teams from teaching hospitals in developing nations. In its 6 years of operation, it has taught 64 such teams, whose members have in turn taught others in their own countries. This success demonstrates the possibility for a major contribution to promoting breastfeeding.

Breast Feeding↗
PubMed1989

At risk drinkers.

Explore the source record for details and available documents.

Alcohol Drinking↗
PubMed1988

The role of vasopressin as an antipyretic in the ventral septal area and its possible involvement in convulsive disorders.

Perfusion of the peptide, arginine vasopressin (AVP), within the ventral septal area (VSA) of the brain of a number of species reduces fever but not normal body temperature. This antipyretic response appears to be mediated by AVP receptors of the V1 subtype. Lesions of the VSA with kainic acid are associated with prolonged and enhanced fevers in rats. A role for endogenous AVP in fever suppression within the VSA comes from several types of experiments: (1) AVP release within the VSA is inversely correlated to fever height; (2) AVP antagonists or antiserum injected into the VSA prolong fever; (3) animals lacking endogenous AVP in the VSA (Brattleboro rat, long-term castrated rat) develop enhanced fevers. Electrical stimulation of the AVP-containing cell bodies of the bed nucleus of the stria terminalis (BST) orthodromically inhibits VSA neurons and also suppresses fever; the latter effect can be abolished with application of a V1 antagonist to the VSA. Iontophoretic studies indicate that AVP inhibits glutamate-stimulated activity of thermoresponsive and other VSA neurons. AVP can also act in the VSA to cause severe motor disturbances; this action is receptor mediated and increases in severity upon sequential exposure to AVP. Because sites of action of the antipyretic and convulsive action of AVP are similar, and because animals lacking brain AVP display reduced convulsive activity, it is possible that AVP, released during fever, could be involved in the genesis of convulsive activity.

Action Potentials↗
PubMed1987

Providing professional lactation management consultation.

The probability of successful lactation and breastfeeding can be maximized by professional lactation management consultant services such as those provided by the San Diego Lactation Program. There are four distinct service components of the program: prenatal guidance; skilled immediate postpartum assistance; a telephone consultation service; and evaluation of lactation progress and problem solving in a special lactation clinic. To insure the best care for the mother-infant couple, these services must be provided by health care professionals with "hands-on" backgrounds in one of the perinatal specialties (M.D. or R.N.) as well as knowledge and skills in the specific area of lactation. Teaching hospital-based lactation programs such as the San Diego model can offer both consultant services and provide a much needed learning opportunity in lactation and breastfeeding management for such health professionals.

Breast Feeding↗