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The interrelationships between physicochemical properties, absorption and potency of 2-desoxoparaherquamide and five analogs, representing a new anthelmintic class, were evaluated in in vitro and in vivo assays. At pH 7.5, rates of drug absorption by the gastrointestinal nematode Haemonchus contortus and jird small intestine, parameterized by the permeability coefficient, P(e), ranged from 1.2-2.4 x 10(-4) cm/min (nematode) to 2.5-5.5 x 10(-3) cm/min (jird). In the jird intestine, absorption was pH-dependent, with P(e) at pH 7.5 being twice that at pH 4.5, reflecting the negative influence of protonation on transport of these weakly basic molecules. Each compound rapidly paralyzed H. contortus during in vitro exposure to therapeutically relevant concentrations (1-10 microm). The kinetics of drug action on motility in vivo mirrored their in vitro effects; motility concentrations were reduced in nematodes collected from jird stomach 3 h following oral drug dosing, by which time > or =50% clearance of the parasites had occurred. The nematode/medium partition coefficient K ranged from 10.1 to 16.1, consistent with the lipophilic nature of the compounds. The time required to reduce motility in vitro by 50% (t50*) and P(e) were used to determine C(n)*, the concentration of drug in the nematode at t50*, as an indicator of intrinsic potency. In the jird, the apparent potencies of the compounds were insensitive to route of administration (i.e. oral = i.v. = i.p. = i.m.) for H. contortus and two other gastrointestinal nematodes, Ostertagia ostertagi and Trichostrongylus colubriformis; topical administration, however, required three to 10-fold higher doses for equivalent efficacy.

A series of analogues of 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (6), an enone prodrug of the mixed DA D(1)/D(2) agonist 5,6-diOH-DPAT (2), was synthesized. The pharmacological profiles of these new enones and their in vivo pharmacological activities were investigated in the Ungerstedt rat rotation model for Parkinson's disease. At 0.1 mg kg(-1) po, the N-methyl-N-n-propyl (12) and the N-ethyl-N-propyl (13) analogues induced pronounced and long lasting pharmacological effects. The pharmacological profile of enone 12 was found to be similar to that of 6, while enone 13 was significantly more potent than 6 (p < 0.01). Analyses of rat brains after the administration of (-)-6 and 13 indicated the presence of hydroxylated metabolites of the parent enones. It is speculated that such metabolites are alpha'-hydroxylated enones that may constitute the first step in the formation of the corresponding catechols.