Local anesthetic activity and acute toxicity ofN-substituted 1,2,3,4-tetrahydro-1- and 2-naphthylamines

Journal of Pharmaceutical Sciences (Impact Factor: 2.59). 06/1978; 67(6):880-2. DOI: 10.1002/jps.2600670647
Source: PubMed


Seven N-substituted 1,2,3,4-tetrahydro-1- and three 2-naphthylamines were prepared and tested for local anesthetic activity in the rabbit corneal reflex test and the mouse sciatic nerve block test. At 0.1 and 1%, three 1-alkylamino compounds had durations of action comparable to that of tetracaine in the rabbit corneal reflex test and were considerably more potent than lidocaine. The other four 1-alkylamino derivatives were inactive or at best minimally active. The durations of action of 1% concentrations of the three 2-alkylamino compounds were equivalent to that of 1% lidocaine in the corneal reflex test. In the mouse sciatic nerve block test, the three active 1-alkylamino compounds were considerably longer acting than either tetracaine or lidocaine. Three 1-alkylamino and the three 2-alkylamino compounds showed toxicity equal to or greater than lidocaine, while two 1-alkylamino and two 2-alkylamino compounds showed toxicity equal to or greater than tetracaine by the intraperitoneal route in mice. N-Heptyl-1,2,3,4-tetrahydro-6-methoxy-1-naphthylamine methanesulfonate was the most promising local anesthetic in these series.

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    ABSTRACT: N-Heptyl -1,2,3,4- tetrahydro-6-methoxy-1-naphthylamine methanesulfonate (I) is a potent, long lasting local anesthetic. It was as potent as tetracaine and at least 10 times more potent than lidocaine in the rabbit corneal reflex, guinea pig wheal, and mouse sciatic nerve block tests. The threshold anesthetic concentration (TAC), defined as the concentration required to produce anesthesia lasting 5 min, was calculated from each linear regression line fitted to the log dose-duration data, and these values were used to compare the potencies of the local anesthetics. In the rabbit corneal reflex test, the TAC values were 0.04% for I, 0.04% for tetracaine, and 0.66% for lidocaine. In the guinea pig wheal test, I had a TAC of 0.02%, which was equipotent to tetracaine and 11 times more potent than lidocaine; epinephrine (1:100,000) prolonged the duration of action of all three local anesthetics but had the least effect with I. In the mouse sciatic nerve block test, the TAC values were 0.06% for I, 0.10% for tetracaine, and 0.86% for lidocaine. The acute LD50 values of I in mice were 138 mg/kg sc and 26 mg/kg iv. By either route, I was less toxic than tetracaine and more toxic than lidocaine. Comparison of the LD50 and TAC values in the mouse sciatic nerve block test indicated that I had a greater therapeutic index than either reference standard.
    Journal of Pharmaceutical Sciences 05/1978; 67(6):882 - 884. DOI:10.1002/jps.2600670648 · 2.59 Impact Factor
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    ABSTRACT: This report introduces a simple and easy technique for animal handling and drug administration into the sciatic nerve area for determining local anesthesia and neuromuscular blocking activity in mice. The drugs were injected into the popliteal space of the right hindlimb (i.e., the sciatic nerve area). The loss of motor activity of the right hindlimb was taken as a sign of producing local anesthesia. A positive local anesthetic activity was recorded when a mouse was only able to walk using three limbs on an inverted wire mesh screen and the injected limb was hanging in the air. This method is superior to the commonly used techniques of applying drugs to the rabbit's cornea, the guinea pig's back skin, or the root of the mouse tail to determine the reduced reflex responses and to assess the local anesthetic activity. The present method has evaluated a number of drugs (cocaine, lidocaine, procaine, propranolol, quinidine, quinacrine, verapamil, and diltiazem), which are known to produce local anesthesia. The sciatic nerve blockade technique is also capable of determining neuromuscular blocking activity of drugs, in which the end point of activity taken is different from that for local anesthetic drugs. The method reported here has been validated by reference neuromuscular blocking agents (d-tubocurarine, decamethonium, and succinylcholine). A positive neuromuscular blockade was recorded when a mouse was unable to stay on the inverted wire mesh screen. The information provides not only the local anesthetic or neuromuscular blocking potency of drugs but also duration of action of drugs.
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    Pharmacological Research 06/2000; 41(5):539-42. DOI:10.1006/phrs.1999.0619 · 4.41 Impact Factor