ABSTRACT
The enantiomers desoxymuscarine 6 were tested in vitro on guinea pig tissues, and their muscarinic potency was evaluated at M2 (heart force and rate) and M3 (ileum and bladder) receptor subtypes together with the enantiomers of the parent compound muscarine 1. The eutomers (+)-1 and (+)-6 and distomers (-)-1 and (-)-6 were also assayed in vivo on pithed rat. Affinity, relative efficacy and enantio-selectivity were also determined for the compounds under study at M2 (heart force and rate) and M3 (ileum and bladder), in order to investigate muscarinic receptor heterogeneity. The results of this study have been discussed in comparison with the data previously reported for the structurally related fluoromuscarine (+)-4 and difluoromuscarines (+)-5 and (-)-5.
Subject(s)
Muscarine/analogs & derivatives , Muscarinic Agonists/pharmacology , Animals , Guinea Pigs , Heart Rate/drug effects , Ileum/drug effects , In Vitro Techniques , Male , Muscarine/pharmacology , Muscarinic Agonists/isolation & purification , Muscle Contraction/drug effects , Myocardial Contraction/drug effects , Rats , Receptor, Muscarinic M2 , Receptor, Muscarinic M3 , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/physiology , Stereoisomerism , Structure-Activity Relationship , Urinary Bladder/drug effectsABSTRACT
The present study evaluates whether some of the irreversible effects induced by neonatally administered capsaicin are present in offspring prenatally treated with the neurotoxin as well, and investigated its foetal toxicity. Capsaicin was administered subcutaneously at doses of 50, 100 and 200 mg/kg in five injections every other day between gestational days 7-15, the period of major organogenesis, or in a single subcutaneous injection of 50 mg/kg only at day 15 of gestation. In one-month old rats prenatally capsaicin-treated the response to noxious stimulation (hot plate and wiping tests) and the urinary excretion in response to oral water load were evaluated. Parallel experiments were conducted in one-month old rats treated with capsaicin (50 mg/kg) on the 2nd day of life. Prenatal capsaicin induced no evident treatment-related signs of toxicity in dams and offspring, nor did it influence the body growth of the pups or induce cutaneous lesions. Unlike neonatal treatment, prenatal administration of neurotoxin did not raise the threshold to thermal and chemical pain, and did not modify diuresis induced by oral load. Since researchers have proposed the existence of more than one population of capsaicin-sensitive afferent neurones which differ in their age-dependent sensitivity to capsaicin, we hypothesized that failure of prenatal treatment might be due either to reduced foetal availability, not capable of selectively destroying capsaicin-sensitive neurones, or to incomplete rearrangement and maturation of developing primary sensory neurons, in fact, the existence is well known of more than one population of capsaicin-sensitive afferent neurons which differ in their age-dependent sensitivity to capsaicin. Future studies are needed to elucidate the effects of capsaicin at cellular and molecular levels.
