2.445 A summary of the in vitro pharmacology of pardoprunox (SLV308): A novel dopamine D2/D3 partial agonist and 5-HT1A agonist for the treatment of Parkinson's disease

In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): A novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist

“…Consistent with D 2 receptor antagonism SLV308 antagonized apomorphine-induced climbing behavior in mice and reduced amphetamine-induced locomotor activity ((McCreary et al, 2006b;personal observation). Further, studies in the MPTP-treated common marmoset suggest that SLV308 reverses MPTP-induced disability and reverses the reduction in locomotor activity (McCreary et al, 2006b) suggesting putative antiparkinsonian-like efficacy. Moreover, SLV308 did not prime for dyskinesias in MPTPtreated marmosets (Johnston et al, 2005).…”

“…In addition to the putative partial agonists actions of SLV308 seen in vitro extensive in vivo studies demonstrate that SLV308 is also a partial agonist in vivo. SLV308 stimulated turning behavior in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta and submaximally (vs. quinpirole) decreased dialysate dopamine levels in the rat nucleus accumbens in contrast to terguride (McCreary et al, 2003;2006b). Consistent with D 2 receptor antagonism SLV308 antagonized apomorphine-induced climbing behavior in mice and reduced amphetamine-induced locomotor activity ((McCreary et al, 2006b;personal observation).…”

“…SLV308 stimulated turning behavior in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta and submaximally (vs. quinpirole) decreased dialysate dopamine levels in the rat nucleus accumbens in contrast to terguride (McCreary et al, 2003;2006b). Consistent with D 2 receptor antagonism SLV308 antagonized apomorphine-induced climbing behavior in mice and reduced amphetamine-induced locomotor activity ((McCreary et al, 2006b;personal observation). Further, studies in the MPTP-treated common marmoset suggest that SLV308 reverses MPTP-induced disability and reverses the reduction in locomotor activity (McCreary et al, 2006b) suggesting putative antiparkinsonian-like efficacy.…”

“…However, the current data suggests that SLV308 is less potent at 5-HT 1A receptors compared to 8-OH-DPAT in spite of the high binding affinities of both ligands for this receptor. This degree of 5-HT 1A receptor agonism in vitro did translate into to 5-HT 1A mediated behavior in vivo (McCreary et al, 2006b), which was blocked by the 5-HT 1A antagonist WAY100635. The effects of terguride have been assessed on 5-HT 1A receptors in vitro where it was demonstrated that terguride possessed partial efficacy at the receptor [intrinsic efficacy is 71%, pEC 50 of 7.24; (Newman-Tancredi et al, 2002b)], but when in vivo studies were conducted no putative agonist actions were observed (McCreary et al, unpublished).…”