Assuntos
Desenho de Fármacos , Indústria Farmacêutica/tendências , Genoma Humano , Genômica/tendências , Indústria Farmacêutica/métodos , Humanos , Receptores Colinérgicos/genética , Receptores Colinérgicos/fisiologia , Receptores Histamínicos/genética , Receptores Histamínicos/fisiologia , Receptores Opioides/genética , Receptores Opioides/fisiologia , Receptores Purinérgicos/genética , Receptores Purinérgicos/fisiologiaRESUMO
Geoff Burnstock's remarkable insight and tenacity has established the area of purinergic research as a bona fide target for drug discovery. While efforts in P1 receptor-based medicinal chemistry and biology efforts over the past 25 years have not reached the level of success that the pharmaceutical industry investment may have anticipated, the P2 area, with knowledge of the selective localization of members of the P2X and P2Y family members and data from transgenic knockouts, has identified several potential therapeutic areas of major promise including cystic fibrosis, chronic bronchitis, male contraception and neurodegeneration. In addition, interest in the potential of purinergic therapeutics has extended outside the major pharmaceutical companies to the 'biotech industry' resulting in an environment where the inherent risks of 'first in field' in a therapeutic area may be more appropriately nurtured.
Assuntos
Purinas/metabolismo , Receptores Purinérgicos/fisiologia , Animais , Indústria Farmacêutica , Humanos , Receptores Purinérgicos/efeitos dos fármacosRESUMO
The effects on nociception, motor and autonomic function produced by the intrathecal administration of three adenosine analogs: N6-(L-2-phenylisopropyl)-adenosine, N6-cyclohexyladenosine and 5'-(N-ethylcarboxamido)-adenosine were examined in rats. Over the range of 0.3 to 1.0 nmol these agents produced a dose-dependent antinociception in the hot plate and tail-flick tests. In addition, 5'-(N-ethylcarboxamido)-adenosine and N6-(L-2-phenylisopropyl)-adenosine both suppressed the chemically evoked writhing response as well as the touch-evoked hyperesthesia normally observed in rats receiving low doses of intrathecal strychnine. These adenosine analogs examined at doses higher than 1.5 nmol produced a dose-dependent motor impairment as measured behaviorally and by electromyography, and an increase in the volume distention required to evoke micturition. Statistically significant effects on heart rate or blood pressure were not observed at any of the doses tested. The effects of the adenosine analogs on nociceptive and motor endpoints were partially antagonized by pretreatment with intrathecal caffeine (2 mumol). These results suggest a probable association of spinal adenosine receptors with a number of spinal sensory and motor systems other than those involved with nociceptive processing.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Movimento , Dor/fisiopatologia , Receptores Purinérgicos/fisiologia , Medula Espinal/fisiologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina-5'-(N-etilcarboxamida) , Animais , Pressão Sanguínea/efeitos dos fármacos , Cafeína/farmacologia , Masculino , Fenilisopropiladenosina/farmacologia , Ratos , Ratos Endogâmicos , Bexiga Urinária/fisiologiaRESUMO
A computer-assisted densitometer which consists of a darkroom enlarger, a black-and-white exposure meter, an amplifier, an analog-to-digital converter, and a microcomputer with a monitor and a graphic printer can be utilized for the quantitative analysis of autoradiograms. QUANTAR, a computer program written in BASIC, records the density measurements and stores the data in a file that can be easily retrieved by commercially available spreadsheet software. A spreadsheet template was designed to convert the digital readings into concentration of ligand in tissue. A variety of spreadsheet templates can be created to analyze data for a standard curve, a Scatchard plot, or a binding competition curve. This system, which is easy to assemble, may be useful to the frugal investigator with a modest equipment budget.
Assuntos
Autorradiografia/instrumentação , Densitometria/instrumentação , Diagnóstico por Computador/instrumentação , Software , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Densitometria/economia , Diagnóstico por Computador/economia , Receptores Purinérgicos/fisiologia , Substância Gelatinosa/metabolismoRESUMO
A comparison of the effect of the putative adenosine 5'-triphosphate (ATP) antagonist, reactive blue 2, was made on the inhibitory responses to exogenous purines and non-adrenergic, non-cholinergic nerve stimulation in the rabbit portal vein, a preparation possessing both P1- and P2Y-purinoceptors, and on the excitatory responses to alpha, beta-methylene ATP in the rat portal vein where P2X-purinoceptors are present. In the ergotamine-contracted rabbit portal vein, ATP, adenosine and isoprenaline induced concentration-dependent relaxations. Reactive blue 2 (10-50 microM) produced a 2-9-fold shift to the right of the concentration-response curve to ATP, while the responses to adenosine and isoprenaline were not significantly altered. The inhibition of ATP assessed in the concentration-response curves appeared to be non-competitive. Electrical field stimulation of the ergotamine-contracted rabbit portal vein produced frequency-dependent relaxations that were abolished following incubation with tetrodotoxin (1 microM) and were inhibited by reactive blue 2 (30-50 microM), in a concentration-dependent manner. The rat portal vein contracted in response to the application of exogenous noradrenaline and alpha, beta-methylene ATP. Responses to both alpha, beta-methylene ATP (a P2X-purinoceptor agonist) and noradrenaline were not significantly inhibited by concentrations of reactive blue 2 that produced inhibition of the P2Y-mediated responses of the rabbit portal vein. In conclusion, it is suggested that reactive blue 2 is a non-competitive P2Y-purinoceptor antagonist, although the drug has a narrow range of activity and non-specific side effects become apparent at high concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)